The Potential of Anti-coronavirus Plant Secondary Metabolites in COVID-19 Drug Discovery as an Alternative to Repurposed Drugs: A Review

In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and the aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.

#

Key words

SARS-CoV-2 - antivirals - phytochemicals - natural products - medicinal plants - alternative medicine

Abbreviations

(h)ACE2: (human) angiotensin converting enzyme 2

3CLpro: 3-chymotrypsin-like protease

COVID-19: coronavirus disease 2019

CQ: chloroquine

E: envelope

EC₅₀ : half maximal effective concentration

ECG: (−)-epicatechingallate

EGC: (−)-epigallocatechin

EGCG: (−)-epigallocatechin-3-gallate

FMF: familial Mediterranean fever

HCQ: hydroxychloroquine

IC₅₀ : half maximal inhibitory concentration

M: membrane

MD: molecular dynamics

MERS-CoV: Middle East respiratory syndrome coronavirus

Mpro: main protease

N: nucleocapsid

NRBD: N-terminal RNA binding domain

PLpro: papainlike protease

RBD: receptor-binding domain

RdRp: RNA-dependent RNA polymerase

S: spike

SARS-CoV: severe acute respiratory syndrome coronavirus

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

SM(s): secondary metabolite(s)

TMPRSS2: transmembrane serine protease 2

Introduction

The first COVID-19 case was identified in December 2019 in Wuhan, China. This was the beginning of one of the greatest pandemics facing humanity in modern times. This virus, later named SARS-CoV-2, is responsible for more than 6 million fatalities worldwide to date (March 1, 2023) [1].

SARS-CoV-2 with crown-shaped glycoproteins on its surface has a single-stranded RNA of 26.4 – 31.7 kb, which shares 80% of its genome with the SARS-CoV virus [2], [3], [4], [5], [6], [7], [8], [9].

Given the vast dispersion and high fatality rate of the virus, scientists and research institutes all over the world have been searching for an effective treatment to manage the disease [10], [11], [12].

While antiviral drug development has grown and vaccines have become accessible, there remains a demand for cost-effective and easily applicable treatment approaches to combat COVID-19 [13]. The creation of broad-spectrum coronavirus inhibitors, which can be administered orally or via inhalation, may play a crucial role in dealing with emerging SARS-CoV-2 variants [13]. Such treatments would be greatly beneficial in the readiness for future outbreaks of pathogenic coronaviruses [13].

In response to the COVID-19 pandemic, much research has been conducted on the structural properties of SARS-CoV-2 proteins and viral-cellular protein complexes to find potential targets for therapeutic interventions [14]. The spike (S) protein, main protease (Mpro), papainlike protease (PLpro), and RNA-dependent RNA polymerase (RdRp) are the most intensively researched pharmacological targets [14]. In general, antiviral drugs against SARS-CoV-2 employ a number of different tactics to prevent viral replication. For example, the SARS-CoV-2 S protein is targeted by potential inhibitors of viral attachment to host cells and human angiotensin converting enzyme 2 (ACE2) receptor interaction-mediated viral entry [15], [16], [17]. Inhibiting viral proteases, Mpro [18], also known as 3-chymotrypsin-like cysteine protease (3CLpro), and PLpro [19], [20], is a different tactic. Moreover, RdRp, an enzyme that facilitates the synthesis of RNA using an RNA template, has been identified as a target for the development of anti-SARS-CoV-2 therapeutics [21]. Therefore, researchers are seeking substances with the aforementioned qualities in order to identify potential antiviral secondary metabolites to combat SARS-CoV-2.

Because there has been limited success in designing, developing, or discovering COVID-19 treatments, clinical and laboratory research is ongoing, most of which is still in an early stage of research [22].

The repurposed antiviral drugs used to treat COVID-19 may provide protection against infection or speed up recovery, but all COVID-19 antiviral drugs currently on the market have drawbacks that may prevent their use by the general public [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. For example, remdesivir administration led to mild to moderate undesirable outcomes, including but not restricted to liver toxicity, queasiness, anemia, kidney impairment, low blood pressure, respiratory collapse, and constipation, among other things [38], [39], [40], [41], [42]. These shortcomings have highlighted the need for new and more targeted medications [43].

Plant-derived compounds have been shown to be efficient against viruses. For example, in 1952, the Boots pharmaceutical company in England tested 288 plants for the first time for their antiviral properties against influenza A [44]. According to the results of this study, 12 of the examined plants showed antiviral activity [44]. To date, hundreds of plants with antiviral properties have been identified and used for direct antiviral effects or to alleviate symptoms of viral diseases [45], [46], [47]. More recently, Guerra et al. conducted a comprehensive review of reports focusing on plant-derived compounds as potential inhibitors of the SARS-CoV-2 proteases [48]. Their findings indicated that flavonoids constitute a significant portion of these compounds, with quercetin emerging as the molecule with the highest number of reports, followed by kaempferol [48].

In response to the COVID-19 pandemic, Thailandʼs Ministry of Health has authorized the utilization of Andrographis paniculata, also known as green chiretta, as a pilot program to address the initial phases of COVID-19 [49]. This initiative was implemented during a surge in the coronavirus outbreak in the Southeast Asian nations, with the aim of providing an alternative treatment option to alleviate the severity of the outbreak and decrease treatment expenses [49].

To defend themselves against biotic and abiotic stresses including pests, microorganisms, and environmental conditions, plants produce structurally diverse low-molecular-weight compounds called secondary metabolites or specialized metabolites (SMs) [50], [51]. Based on their chemical structure, SMs are classified as phenolic compounds (e.g., flavonoids), terpenoids, sulfur-containing compounds (e.g., glucosinolates), and nitrogen-containing compounds (e.g., alkaloids) [52]. In this review, we have compiled the latest data on the potential antiviral properties of plant SMs and their mode of action against SARS-CoV-2. We conducted a search of the Google Scholar, PubMed, and Science Direct databases using terms such as phytochemical, plant-derived compounds, plant compounds, and secondary metabolites, in conjunction with antiviral, SARS-CoV-2, and coronavirus. Our search focused on original papers reporting in vitro, in vivo, and in silico studies from the emergence of SARS-CoV-2 in December 2019. To retrieve a comprehensive list of phytochemicals that have demonstrated inhibitory properties against drug targets with high similarity between SARS-CoV-2 and related viruses, we conducted additional searches using terms such as SARS-CoV and MERS-CoV. This approach enabled us to identify potential candidates for further investigation and development as antiviral agents against SARS-CoV-2. Additionally, we incorporated the terms classification and structure to explore the structural properties and classification of these compounds. The presented data may provide a new approach for designing and developing future antiviral drugs.

#

Classification of SARS-CoV-2

On January 12, 2020, China disclosed the genetic sequence of SARS-CoV-2 for use in diagnostic kits in other countries [53]. Researchers classified this virus by using a viral classification system after evaluating its sequence [54]. Similar to SARS-CoV and MERS-CoV, SARS-CoV-2 belongs to the genus betacoronavirus, subfamily Orthocoronavirinae, and family Coronaviridae. The subfamily Coronavirinae is divided into the genera alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus based on genomic sequence, with betacoronaviruses and alphacoronaviruses being human-pathogenic [55].

SARS-CoV-2 is classified as lineage B based on its greater similarity to SARS-CoV (79.5% sequence homology) compared to other betacoronaviruses such as MERS-CoV (50% sequence homology) [56]. Another finding supporting this classification is that the seven ORF1ab domains of SARS-CoV-2 have a 94.6% similarity to those of SARS-CoV, compared to less than 90% for other betacoronaviruses [57]. The reproductive number (R, which determines how infectious the agent is) is significantly higher for SARS-CoV-2 (2.9) compared to SARS-CoV R (1.77) [58], [59].

The coronaviridae study group (CSG) first classified these three viruses, SARS-CoV-2, SARS-CoV, and MERS-CoV, as distinct species within a new, informal subclass of the genus betacoronavirus [60], [61]. When subgenus rank was established in virus classification, these three informal subgroups were introduced as the three subgenera Sarbecovirus, Embecovirus, and Merbecovirus, respectively, and unique names were defined for these viruses and their species according to virus classification practice [62]. To date, five concerning SARS-CoV-2 variants have been identified: alpha, beta, gamma, delta, and omicron [63], [64].

#

SARS-CoV-2 Structure and COVID-19 Drug Targets

The genome of SARS-CoV-2 is a 30 kb single-stranded positive-sense RNA [56]. This virus shares less than 79% nucleotide sequence homology with SARS-CoV [56]. The novel coronavirus, SARS-CoV-2, is distinguished from other betacoronaviruses by its distinct polybasic cleavage sites, which result in increased transmission intensity and pathogenicity [65].

From 5′ to 3′, this virus has six major open reading frames (ORFs) and additional supplementary genes that are translated into replicase (ORF1a/ORF1b), S, envelope (E), membrane (M), and nucleocapsid (N) proteins [66]. In addition, the viral genome has seven sub-ORFs encoding accessory proteins distributed among structural genes [56], [57], [67].

There are 16 nonstructural proteins, 9 accessory proteins, and 4 structural proteins in the SARS-CoV-2 virus [68]. Most of them are of the same length as their SARS-CoV counterparts [56], [57]. The structural and nonstructural proteins of these two viruses exhibit 90% and 85% similarity, respectively [69].

SARS-CoV-2′s major therapeutic targets are S, 3CLpro or Mpro, and RdRp [70]. E proteins, M proteins, N proteins, helicase proteins, and PLpro are other potential therapeutic targets for developing or repurposing drugs to treat the COVID-19 disease [70].

It is worth noting that several host proteins can be utilized as therapeutic targets due to their roles in processes such as virus binding to host cells or viral protein activation. Angiotensin-converting enzyme 2 (ACE2) [71], [72], transmembrane serine protease 2 (TMPRSS2) [73], [74], [75], [76], cathepsin L [77], and furin [78] are among the host proteins that can be used as COVID-19 drug targets.

#

Current Treatments for COVID-19 Disease

To date, numerous studies have been conducted on the application of repurposed medicines that can be effective for the treatment of COVID-19. Among the various drugs introduced as a remedy, only a few have been approved by the US Food and Drug Administration (FDA) based on their safety and efficacy (https://www.fda.gov/drugs/emergency-preparedness-drugs/coronavirus-covid-19-drugs). The complete list of approved drugs is provided in [Table 1].

Table 1 List of FDA-approved synthetic drugs against COVID-19, their mechanism of action, and probable side effects.
Name of Drug	Mechanism of Function	Side Effects	Reference/s
Remdesivir (Veklury)	Inhibition of viral replication	Headache, nausea, affecting blood tests	[23], [24], [25], [26]
Tocilizumab (Actemra) and Infliximab/Tocilizumab	Tocilizumab as an antagonist for interleukin-6 (IL-6) receptor acts as an anti-inflammatory agent in patients with cytokine storm	No side effect in initial studies, enhancement of liver enzymes in the case of infliximab/tocilizumab	[27]–[23]
Baricitinib (Olumiant)	Inhibition of virus infection and acting as an anti-inflammatory agent	Vein thrombosis	[30], [31]
Paxlovid (Nirmatrelvir-Ritonavir)	Inhibition of viral replication	Headache, diarrhea, vomiting dysgeusia	[32]
Molnupiravir (Lagevrio)	Inhibition of virus multiplying	Dizziness, rash, diarrhea, nausea	[33], [34]
Kineret (anakinra)	Inhibition of interleukin-1 (IL-1) receptor	Reaction in injection site, enhancement of liver enzymes, hypertension	[35], [36]
Gohibic (Vilobelimab)	Vilobelimab as an antagonist od complement component 5a (C5-a) receptor, acts as anti-inflammatory agent	Hypertension, pneumonia, pulmonary embolism, delirium, and sepsis	[37]

#

Prioritizing Potential Candidates for Anti-SARS-CoV-2 Drug Development and Discovery from Phytochemicals and Plant Secondary Metabolites

Numerous research studies have looked into the potential of phytochemicals as anti-COVID-19 drug candidates. However, with the plethora of compounds available, it is crucial to establish a rational approach to prioritize the most promising candidates for further investigation. This section aims to provide guidelines for prioritizing the compounds with the highest likelihood of exhibiting potent antiviral effects against SARS-CoV-2.

In silico screening and molecular docking studies

Drug design and discovery is a time-consuming and resource-intensive process. Traditional methods often fall short, leading to the introduction of modern computer-aided drug design (CADD) approaches aimed at reducing time and cost [79].

Molecular docking and molecular dynamics (MD) simulations are commonly employed methods in CADD for identifying and repurposing potential drugs against various life-threatening diseases [80], [81]. These techniques enable researchers to study the behavior of small chemical entities in the active sites of target proteins and determine their activity [82].

Molecular docking calculations focus on identifying the active site regions of receptors to determine ligand–receptor interactions and find the optimal binding modes. As discussed, in the case of COVID-19, the main drug targets for molecular docking are Mpro, PLpro, and RdRp, crucial proteins involved in viral replication and transcription.

Despite its merits, there are several limitations to the application of molecular docking in drug discovery. Scoring functions struggle to accurately predict binding energies due to challenges with certain intermolecular interaction terms [83]. Significant interactions like halogen bonding and guanidine–arginine interactions are often ignored [84], [85]. Handling water molecules in binding pockets is problematic due to a lack of hydrogen coordinates and theoretical approaches [86]. Additionally, failing to account for protein conformational changes due to a rigid receptor could lead to inaccurate negative findings [87]. Furthermore, assessing off-target activity is a challenge typically addressed through animal and human trials [82], [86]. These limitations highlight the need for ongoing research and improvement in molecular docking.

MD simulations, as an in silico computational approach, enable the prospective estimation of temporal system evolution and, consequently, anticipate the MD within the system [88]. This technique provides insights into the dynamic interactions between molecules and their target proteins.

Using MD simulations can be a useful tool in discovering drugs for COVID-19, but their limitations may impact their dependability and precision. These limitations arise from the current inadequacies of the force fields used in simulations [89], [90]. The force fields often overlook critical factors such as polarization effects, charge transfer, electronic-based interactions, including π−π and cation−π interactions, and halogen bonds [91]. To improve the accuracy of free-energy predictions, future developments will likely incorporate polarizable force fields and quantum mechanical calculations [91]. Furthermore, prolonging the duration of simulations to micro- and millisecond intervals can produce more reliable outcomes that correspond with real-life experimental situations [92].

Moreover, the accuracy of these simulationsʼ application to complex target families like metalloproteins is limited [91]. Additionally, when utilizing MD simulations, there can be difficulties due to the lack of standardized protocols, inadequate analytical resources, and the management of extensive trajectory data [93].

A study conducted by Kumar et al. serves as an illustrative instance wherein a combination of methodologies, including molecular docking and MD simulations, were employed to identify potential inhibitors targeting the main Mpro of SARS-CoV-2 [94]. Notably, the study successfully identified three novel natural metabolites, namely ursolic acid, carvacrol, and oleanolic acid, which exhibited stable and high binding energies with the Mpro protein [94]. Furthermore, the compounds were found to comply with the principles of absorption, distribution, metabolism, and excretion (ADME), as well as Lipinskiʼs rule of five, ensuring their pharmacological viability [94].

Despite the extensive computational exploration of various drugs for COVID-19, experimental methods remain irreplaceable in the identification of promising drug candidates [95]. In vitro experiments are needed to validate results of in silico studies, including assessing antiviral effects in infected human lung cells. In vivo studies using SARS-CoV-2 animal models are necessary for confirming inhibitory potential. However, only a few compounds have been tested in both in vitro and in vivo settings.

Nevertheless, by using meticulously curated prior experimental data and employing rigorous computational tools, it is possible to facilitate the successful discovery of viable drug candidates through experimental means.

#

Experimental validation and in vitro studies

Antiviral compounds are evaluated by monitoring their cytopathic effects in different cell lines [96]. In vitro antiviral studies against SARS-CoV-2 involve using cells and organoids. Cell lines such as Vero E6, HEK293T, Calu-3, Huh7, and Caco-2 are used to replicate and isolate the virus and conduct infection experiments. These cell lines provide valuable information about virus replication and infection, although they have limitations in accurately mimicking human physiological conditions.

SARS-CoV-2 mainly invades ciliated and type 2 pneumocyte cells in the human lung [97]. Hence, differentiated primary airway epithelial cells serve as a suitable model, but their restricted lifespan in cell culture needs improvement [98].

Moreover, Vero E6, a kidney cell line derived from African green monkeys, is commonly used due to its high susceptibility to SARS-CoV-2 and expression of key entry receptors [96]. However, cell lines derived from animals are insufficient, particularly for evaluating antiviral prodrugs like nucleos(t)ide inhibitors that necessitate metabolic stimulation in human cells [99], [100].

Organoids consist of various types of cells and replicate the physiological characteristics of human organs [101]. Due to their capacity for self-replication, organoids are well suited for extensive drug discovery and disease research screenings [101]. They offer insights into SARS-CoV-2 infection on human tissues and aid in evaluating antiviral effects of compounds [102].

#

In vivo and clinical studies

As noted in the preceding parts and [Table 2], numerous in silico and in vitro studies have assessed the effectiveness of plant SMs against SARS-CoV-2. However, there remains a shortage of adequate in vivo and clinical research to establish the efficacy of plant SMs in preventing viral infections or reducing symptoms associated with viral infections [103]. In reality, several compounds that exhibit strong antiviral activity in laboratory settings may prove to be ineffective in pre-clinical or clinical trials [104].

Table 2 Plant SMs with potential inhibitory effects against SARS-CoV-2 and SARS-CoV.
Chemical superclass	Chemical class	Metabolite(s)	Plant	Virus	Study	Function	Ref.
Alkaloids	Amaryllidaceae alkaloid	Lycorine	Lycoris radiata	SARS-CoV SARS-CoV-2	In vitro	Anti-SARS-CoV activity (EC₅₀: 15.7 nM); Anti-SARS-CoV-2 activity due to reduction of viral RNA levels (EC₅₀: 0.31 µM) and cytopathic effects; Reduction of N protein production.	[188], [226]
	Benzylisoquinoline alkaloid	Tetrandrine	Stephania tetrandra	SARS-CoV-2	In vitro	Calcium channel blocker; Dose-dependent prevention of the SARS-CoV-2 pseudotyped virus entry.	[4]
	Benzylisoquinoline alkaloid	Cepharanthine	Stephania spp.	SARS-CoV-2	In vitro	Inhibition of ACE (0.98 mmol/L); Limiting the SARS-CoV-2 pseudotyped virus entry (IC₅₀: 2.8 µM); Reduction of the viral RNA quantity ensuing authentic virus infection.	[227], [228], [229]
	Benzylisoquinoline alkaloid	Berberine	Berberis petiolaris, Berberis vulgaris	SARS-CoV-2	In vitro	Reduction of viral production (EC₅₀: 10.6 µM); Reduction of viral production (EC₅₀: 2.1 µM).	[230], [231]
	Bisbenzylisoquinoline alkaloid	Berbamine	Berbaris amurensis	SARS-CoV-2	In vitro	Interference with the activity of 2-E protein channels (IC₅₀: 111.5 µM); Cellular defense against cytopathic effects (IC₅₀: 34.34 µM), Reduction of virus replication (EC₅₀: 14.5 µM), Reduction of titers and levels of viral RNA (EC₅₀: 2.4 µM); Preventing the introduction of the SARS-CoV-2 pseudotyped virus.	[232], [233]
	Bisbenzylisoquinoline alkaloid	Liensinine	Nelumbo nucifera	SARS-CoV-2	In vitro	Preventing the entry of the SARS-CoV-2 pseudotyped virus (EC₅₀: 11.52 µM).	[234]
	Bisbenzylisoquinoline alkaloid	Neferine	Nelumbo nucifera	SARS-CoV-2	In vitro	Reduction of the viral RNA quantity ensuing authentic virus infection; Preventing the entry of the SARS-CoV-2 S pseudotyped virus (EC₅₀: 0.36 µM); Inhibition of Ca²⁺-dependent membrane fusion of pseudotyped virus with cells.	[234]
	Bisbenzylisoquinoline alkaloid	Hernandezine	Thalictrum hernandezii, Thalictrum fendleri	SARS-CoV-2	In vitro	Blocking the host calcium channels, followed by inhibiting Ca²⁺-membrane fusion and suppressing virus entry; Limiting the SARS-CoV-2 pseudotyped virus entry (EC₅₀: 0.111 µM).	[227]
	Bisindole alkaloid	Strychnopentamine	Strychnos usambarensis	SARS-CoV-2 MERS-CoV	In silico In vitro	High binding affinity exhibition toward the RdRp enzyme (− 9.4 kcal/mol).	[235]
	Bisindole alkaloid	10′–Hydroxyusambarensine	Strychnos usambarensis	SARS-CoV-2	In silico	High binding affinity exhibition toward the RdRp enzyme (− 10.1 ± 0.38 kcal/mol).	[235]
	Cephalotaxus alkaloid	Homoharringtonine	Cephalotaxus harringtonia	SARS-CoV-2	In vitro	Reduction of viral copy number (EC₅₀: 2.14 µM); Reduction of cytopathic effects (EC₅₀: 3.125 µM); Reduction of infectious virus (EC₅₀: 2.55 µM).	[236]
	Indole alkaloid	Cryptospirolepine	Cryptolepis sanguinolenta	SARS-CoV-2 SARS-CoV MERS-CoV	In silico In vitro Clinical trial	Favorable binding affinity exhibition toward the RdRp enzyme (− 10.5 – 0.57 kcal/mol); Favorable binding affinity exhibition toward the Mpro of SARS-CoV and MERS-CoV.	[190], [235]
	Indole alkaloid	Reserpine	Rauvolfia serpentine	SARS-CoV-2	In vitro	Reduction of viral double-stranded RNA production (EC₅₀: 29.2 µM).	[237]
Alkaloids	Indole alkaloid	Indigodole B	Strobilanthes cusia	HCoV-NL63	In vitro	Reduction of viral yield (IC₅₀: 2.60 µM); Virucidal activity (IC₅₀: 2.09 µM).	[238]
Isoquinoline alkaloid	Isoliensinine	Nelumbo nucifera	SARS-CoV-2	In vitro	Preventing the entry of the SARS-CoV-2 pseudotyped virus (EC₅₀: 3.31 µM (CC).	[234]
Isoquinoline alkaloid	Emetine	Psychotria ipecacuanha	SARS-CoV-2	In vitro Clinical trial	Increase in oxygen levels; Reduction of viral RNA quantity (EC₅₀: 0.147 nM); Reduction in cytopathic effects (EC₅₀:1.56 µM); Reduction of viral titer (EC₅₀: 0.46 µM), and viral RNA levels (EC₅₀: 0.5 µM); Significant inhibition of viral replication (EC₅₀: 0.007 M) observed in pre-virus Vero cells; Inhibition of viral entry in Vero cells; Pre-drug therapy prevents viral entry (EC₅₀: 0.019 M) (pragmatic randomized clinical trial).	[228], [236], [239], [240], [241]
Isoquinoline alkaloid	Somniferine	Withania somnifera	SARS-CoV-2	In silico	High binding affinity exhibition toward Mpro (IC₅₀: 9.62 kcal/mol).	[242]
Methylxanthine alkaloid	Caffeine	Paullinia cupana, Coffea canephora, Coffea arabica	SARS-CoV-2	In silico	Prevention of viral entry by inhibiting the synthesis of RBD and the ACE-2 complex; Possible inhibition of Mpro activity to potentially reduce viral replication (− 5.6 ± 0.30 kcal/mol).	[243], [244]
Phenanthraindolizidine alkaloid	Tylophorine and tylophorine analogs	Tylophora indica	SARS-CoV, MERS-CoV	In vitro	Virucidal activity (Prevention of coronavirus replication; Blocking the cytopathic impact that a virus causes in cells in vitro by inducing apoptosis; EC₅₀ values for natural and synthesized tylophorine analogs were 8 – 1468 nM and 5 – 340 nM respectively; Attacking viral RNA.	[245], [246]
Quinazoline alkaloid	Tryptanthrin	Strobilanthes cusia	HCoV-NL63	In vitro	Reduction of viral yield (IC₅₀:1.52 µM). Virucidal activity (IC₅₀: 0.06 µM); Inhibition of PLpro activity and viral RNA replication.	[238]
Indole alkaloid	Indigo	Baptisia tinctoria	SARS-CoV	In vitro	Inhibition of Mpro in the peptide cleavage assay IC₅₀: 300 µM (cell-free assays), 752 µM (cell-based assays).	[247]
Quinoline alkaloid	Quinidine	Cinchona officinalis	SARS-CoV-2	In vitro	Reduction of viral double-stranded RNA production (EC₅₀: 13.3 µM).	[237]
Quinoline alkaloid	Quinine	Cinchona officinalis	SARS-CoV-2	In silico In vitro	Dose-dependent suppression of SARS-CoV-2 infection displayed in various A549-ACE2/TMPRSS2 structures (EC₅₀: 5.58 – 55.82 µM).	[248]
Quinolizidine alkaloid	Oxysophoridine	Sophora alopecuroides	SARS-CoV-2	In vitro	Decreasing viral RNA quantity and cytopathic effects (EC₅₀: 0.18 µM) (CC₅₀ > 40 µM)	[226]
	Tetrahydroxyindolizidine alkaloid	Castanospermine	Castanospermum australe	SARS-CoV-2	In vitro	Reduction of cytopathic effects dose-dependently; Reduction of viral RNA level.	[249]
	Tropane alkaloid	Schizanthine Z	Schizanthus porrigens	SARS-CoV-2	In silico	High binding affinity toward PLpro.	[189]
Phenolic compounds	Cannabinoid	Cannabidiol	Cannabis sativa	SARS-CoV-2	In vitro	Prevention of viral gene expression and reversing some of SARS-impacts CoV-2′s on host gene transcription during viral infection in lung epithelial cells; Increasing the synthesis of interferon and turning on its antiviral signaling pathway.	[250], [251]
Cannabinoid	Cannabigerolic acid	Cannabis sativa	SARS-CoV-2	In silico In vitro	Inhibition of live SARS-CoV-2 entry, as it effectively prevented the infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 S protein.	[252]
Cannabinoid	Δ9-Tetrahydrocannabinol	Cannabis sativa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 10.25 µM).	[250]
Cannabinoid	Cannabidiolic acid	Cannabis sativa	SARS-CoV-2	In silico In vitro	Inhibition of live SARS-CoV-2 entry, as it effectively prevented the infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 S protein.	[252]
Coumarin	Leptodactylone	Boenninghausenia sessilicarpa	SARS-CoV	In vitro	Demonstration of strong protective efficacy against SARS-CoV-infected cells, with a ratio of 60% at 100 mg/ml.	[253]
Coumarin	Tomentin A	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 6.20 µM).	[254]
Coumarin	Tomentin B	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 6.10 µM).	[254]
Coumarin	Tomentin C	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 11.60 µM).	[254]
Coumarin	Tomentin D	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 12.50 µM).	[254]
Coumarin	Tomentin E	Paulownia tomentosa	SARS-CoV SARS-CoV-2	In vitro	Inhibition of PLpro (IC₅₀: 5.0 ± 0.06 µM) in a dose dependent manner.	[254]
Coumarin	Psoralidin	Psoralea corylifolia	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 4.2 ± 1.0 µM).	[255]
Diarylheptanoid	Hirsutanonol	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 105.60 µM); Inhibition of PLpro (IC₅₀: 7.80 µM).	[256]
Diarylheptanoid	Hirsutenone	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 36.20 µM); Inhibition of PLpro (IC₅₀: 4.10 µM).	[256]
Diarylheptanoid	Oregonin	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 129.50 µM); Inhibition of PLpro (IC₅₀: 20.10 µM).	[256]
Diarylheptanoid	Rubranol	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 1 44.60 µM); Inhibition of PLpro (IC₅₀: 12.30 µM).	[256]
Diarylheptanoid	Rubranoside B	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 105.3 µM); Inhibition of PLpro (IC₅₀: 8.00 µM).	[256]
Phenolic compounds	Diarylheptanoid	Curcumin	Curcuma longa	SARS-CoV-2	In vitro Clinical trial	Nano-curcumin decreased IL6 and IL1 expression and serum levels, with a 20% death rate in the curcumin group compared to a 40% mortality rate in the placebo group (randomized clinical trial); Higher capacity to maintain oxygen saturation, earlier symptomatic recovery, fewer deterioration, less red flag indicators, better clinical results, lessen the mortality rate and shorten the hospital stay for patients with mild to severe symptoms (randomized clinical trial); Pseudovirus dose-dependently inhibited by hACE2 on A549; Dose-dependent suppression of A549/hACE2 syncytia; A dose-dependent reduction in the activity of TMPRSS2 and ACE2 Reduction of SARS-CoV-2 RNA levels (EC₅₀: 7.9 µg/ml) in Vero E6 and human Calu-3 cells.	[257], [258], [259], [260]
Diarylheptanoid	Rubranoside A	Alnus japonica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 102.10 µM); Inhibition of PLpro (IC₅₀: 9.10 µM).	[256]
Ellagitannin	Punicalagin	Punica granatum, Terminalia catappa	SARS-CoV-2	In vitro	Inhibition of RBD-hACE2 binding.	[261], [262]
Ellagitannin	Chebulagic acid	Terminalia chebula	SARS-CoV-2	In vitro	Inhibition of S protein, ACE-2, Mpro.	[261]
Gallotannin	Tannic acid	Caesalpinia spinosa, Rhus spp. semialata	SARS-CoV-2	In vitro	Inhibition of TMPRSS (IC₅₀: 22.31 µM) and Mpro (IC₅₀: 13.4 µM).	[225]
Flavonoid (catechin)	Epigallocatechin gallate	Camellia sinensis	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 73.00 µM).	[133]
Flavonoid (catechin)	Gallocatechin gallate	Camellia sinensis	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 47.00 µM).	[133]
Flavonoid (catechin)	Catechin	Camellia sinensis	SARS-CoV-2	In vitro	Virus incubation with catechin, resulted in a dose-dependent decrease in viral titers.	[263]
Flavonoid (catechin)	Epigallocatechin-3-gallate	Camellia sinensis	SARS-CoV-2	In vitro	Prevention of the SARS-CoV-2 pseudotyped virus entry; Blocking receptor-binding domain (RBD)/hACE2 binding; Early addition lowers viral RNA concentration; Inhibition of Mpro (IC₅₀: 7.58 µM); Non-structural protein 15 inhibition (IC₅₀: 1.62 M); Reduction of viral titers (EC₅₀: 0.20 M).	[161], [264], [265], [266]
Flavonoid (catechin)	Theaflavin 3,3′-di-O-gallate	Camellia sinensis	SARS-CoV-2	In vitro	Reduction in ACE2/TMPRSS2 activity; Inhibition of Mpro (IC₅₀ 8.44 g/ml); Reduction of SARS-CoV-2 RNA and titer levels; Inhibition of Cathepsin L. pseudovirus and viral entry.	[259], [265], [266]
Flavonoid (chalcone)	4-Hydroxyderricin	Angelica keiskei	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 26.00 µM); Inhibition of Mpro (IC₅₀: 81.40 µM).	[267]
Flavonoid (chalcone)	Xanthoangelol E	Angelica keiskei	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 1.2 ± 0.4 µM); Inhibition of Mpro activity (IC₅₀: 11.4 ± 1.4 µM)	[267]
Flavonoid (chalcone)	Panduratin A	Boesenbergia pandurata	SARS-CoV-2	In vitro	Inhibition of SARS-CoV-2 (IC₅₀ of 5.30 µM, CC₅₀: 43.47 µM); Inhibition of SARS-CoV-2 pathogenicity in Vero E6 cells with corresponding IC₅₀ values of 3.62 µg/mL (CC₅₀: 28.06 µg/mL) and 0.81 M (CC₅₀: 14.71 µM).	[268]
Flavonoid (chalcone)	4′-O-Methylbavachalcone	Psoralea corylifolia	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 10.10 µM).	[255]
Phenolic compounds	Flavonoid (chalcone)	Isobavachalcone	Psoralea corylifolia	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 7.30 µM).	[255]
Flavonoid (flavanone)	Hesperetin	Aloe barbadensis, Rutaceae family	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 60.00 µM)	[247]
Flavonoid (flavanone)	Naringenin	Citrus spp., Lycopersicum esculentum	SARS-CoV-2 SARS-CoV	In vitro	Targeting TPCs and the Akt/mTOR signaling pathway; Dose-dependent reduction in cytopathic effects; Inhibition of Mpro (IC50: 92 nM); Reduction of cytopathic effects (EC50: 28.35 µg/mL).	[269], [270]
Flavonoid (flavanone)	6-Geranyl-4′,5,7-trihydroxy-3′,5′-dimethoxy- flavanone	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 13.90 µM).	[254]
Flavonoid (flavanone)	3′-O-Methyldiplacol	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 9.50 µM).	[254]
Flavonoid (flavanone)	3′-O-Methyldiplacone	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 13.20 µM).	[254]
Flavonoid (flavanone)	4′-O-Methyldiplacol	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 9.20 µM).	[254]
Flavonoid (flavanone)	4′-O-Methyldiplacone	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 12.70 µM).	[254]
Flavonoid (flavanone)	Diplacone	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 10.40 µM).	[254]
Flavonoid (flavanone)	Mimulone	Paulownia tomentosa	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 14.40 µM).	[254]
Flavonoid (flavanone)	Bavachinin	Psoralea corylifolia, Rutaceae family	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 38.40 µM).	[255]
Flavonoid (flavone glycoside)	Rhoifolin	Rhus succedanea	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 27.45 µM).	[271]
Flavonoid (flavone glycoside)	Baicalin	Scutellaria baicalensis, Scutellaria lateriflora	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 6.41 µM); Reduction of viral RNA level (EC₅₀: 27.87 µM); Inhibition of Mpro (IC₅₀: 83.4); Inhibition of non-structural protein 15 RNAse activity (IC₅₀: 7.98 µM); Inhibition of Mpro (IC₅₀: 34.71 µM).	[170], [172], [173], [264]
Flavonoid (flavone)	Pectolinarin	Cirsium spp., Linaria spp.	SARS-CoV SARS-CoV-2	In vitro	Inhibition of SARS-CoV-2 Mpro (IC₅₀: 51.64 mM); Inhibition of SARS-CoV Mpro (IC₅₀: 37.78 µM).	[133], [173]
Flavonoid (flavone)	Corylifol A	Psoralea corylifolia	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 32.20 µM)	[255]
Flavonoid (flavone)	Baicalein	Scutellaria baicalensis, Scutellaria lateriflora	SARS-CoV-2	In vitro In vivo	Reduction of viral RNA concentration (EC₅₀: 2.94 M); Reduction of viral RNA levels (EC₅₀: 10 µM); Inhibition of Mpro (IC₅₀: 0.39 µM); Reduction of viral RNA concentration (EC₅₀: 2.92 µM); Reduction of cytopathic effects; Reduction of viral load, body weight loss, and cellular inflammation in the lungs in laboratory mice (0.1 – 50 µM); Inhibition of Mpro and RNA polymerization activity of SARS-CoV-2 Mpro (IC₅₀: 4.5 Μm).	[106], [169], [170], [171], [172]
Phenolic compounds	Flavonoid (flavone)	Quercetagetin	Scutellaria baicalensis, Tagetes erecta	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 1.24 µM).	[170]
Flavonoid (flavone)	Scutellarein	Scutellaria spp.	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 5.8 µM) through a protease assay.	[170]
Flavonoid (flavonol glycoside)	Rutin	Fagopyrum esculentum, Rheum spp.	SARS-CoV-2	In vitro	Exhibition of stable binding affinity against S-ACE2 protein through a deubiquitinase inhibition assay.	[272]
Flavonoid (flavonol)	Quercetin	Allium cepa, Vaccinium spp., Torreya nucifera	SARS-CoV SARS-CoV-2	In silico In vitro	Inhibition of SARS-CoV-2 Mpro (K_i ~ 7.00 µM); Inhibition of SARS-CoV Mpro (IC₅₀: 23.80 µM); Favorable binding affinity exhibition toward SARS-CoV S protein (− 8.5 kcal/Mol).	[273], [274], [275]
Flavonoid (flavonol)	Kaempferol	Capparis spinosa, Crocus sativus	SARS-CoV-2 SARS-CoV	In silico In vitro	Reduction of cytopathic effects (EC₅₀: 34.46 µM); Inhibition of Mpro; Inhibition of 3a ion channel of coronavirus; Favorable binding affinity exhibition toward SARS-CoV-2 S protein (− 7.4 kcal/Mol).	[146], [157], [276]
Flavonoid (flavonol)	Myricetin	Ceratonia siliqua, Vaccinium spp.	SARS-CoV-2 SARS-CoV	In vitro Clinical trial	Inhibition of Mpro (IC₅₀: 2.86 µM); Inhibition of non-structural protein 13 by affecting the ATPase activity; Inhibition of the enzymatic activity of SARS-CoV-2 Mpro and interfere the replication of SARS-CoV-2 (IC₅₀: 0.63 µM) in Vero E6 cells.	[170], [277], [278]
Flavonoid (flavanonol)	Dihydromyricetin	Ampelopsis grossedentata	SARS-CoV-2	In vitro	Significant inhibition of viral replication in Vero cells and inhibition of Mpro (IC₅₀: 1.20 µM).	[170]
Flavonoid (flavonol)	Isorhamnetin	Hippophae rhamnoides, Opuntia ficus-indica	SARS-CoV-2 SARS-CoV	In vitro	Limiting the entry of the SARS-CoV-2 pseudotyped virus.	[279]
Flavonoid (flavonol)	Herbacetin	Linum usitatissimum	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 53.90 µM).	[173]
Flavonoid (isoflavone)	Neobavaisoflavone	Psoralea corylifolia	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 18.30 µM).	[255]
Flavonoid (rotenoid)	12α-epi-Millettosin	Millettia usaramensis	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward the RdRp enzyme (− 8.0 kcal/mol).	[280]
Flavonoid (rotenoid)	Usararotenoid A	Millettia usaramensis	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward the RdRp enzyme (− 8.4 kcal/mol).	[280]
Flavonoid glycoside	Vicenin	Ocimum sanctum	SARS-CoV-2 SARS-CoV	In silico In vitro	Favorable binding affinity exhibition toward Inhibition of Mpro (IC₅₀: 8.97 kcal/mol).	[242]
Flavonoid glycoside	Isorientin 4′-O-glucoside 2′′-O-p-hydroxybenzoate	Ocimum sanctum	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (8.55 kcal/mol).	[242]
Homoisoflavonoid	Brazilin	Paubrasilia echinata, Caesalpinia sappan	SARS-CoV-2 SARS-CoV	In vitro	Inhibition of SARS-CoV-2 RBD/hACE2 dose-dependently; Limiting the SARS-CoV-2 pseudotyped virus entry dose-dependently.	[259]
Biflavonoid	Amentoflavone	Torreya nucifera	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 8.3 ± 1.2 µM) dose-dependently.	[275]
Biflavonoid	Bilobetin	Torreya nucifera	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 72.3 ± 4.5 µM) dose-dependently.	[275]
Phenolic compounds	Biflavonoid	Ginkgetin	Torreya nucifera	SARS-CoV		Inhibition of Mpro (IC₅₀: 32.0 ± 1.7 µM) dose-dependently.	[275]
Biflavonoid	Sciadopitysin	Torreya nucifera	SARS-CoV		Inhibition of Mpro (IC₅₀ 38.4 ± 0.2 µM) dose-dependently.	[275]
Lignan	Nordihydroguaiaretic acid	Larrea tridentata	SARS-CoV-2	In vitro	Inhibition of PLpro (IC₅₀: 1.06 µM); Inhibition of non-structural protein 3 (IC₅₀: 1.62 µM).	[281]
Lignan	Savinin	Chamaecyparis taiwanensis	SARS-CoV SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 25.00 µM).	[282]
Lignan glycoside	Phillyrin	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of viral replication (IC₅₀: 63.90 µg/ml) in Vero E6 cells; Reduction of mRNA levels of TNF-α, IL-6, IL-1β, MCP-1, and IP-10, (markers of pro-inflammatory cytokine production).	[283]
Arylnaphtalene lignan	Diphyllin	Cleistanthus collinus	SARS-CoV-2	In vitro	Reduction of SARS-CoV-2 viral titers in Vero cells.	[284]
Arylnaphthalene lactone lignan glycoside	Cleistanthin B	Cleistanthus collinus	SARS-CoV-2	In vitro	Reduction of viral titers (EC₅₀: 6.51 µM).	[284]
Phenolic acid	Ginkgolic acid	Ginkgo biloba	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 1.79 ± 0.58 µM); Inhibition of PLpro (IC₅₀: 16.30 ± 0.64 µM).	[285]
Phenolic acid	Anacardic acid	Anacardium occidentale	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 2.07 ± 0.35 µM); Inhibition of PLpro (IC₅₀: 17.08 ± 1.30 µM).	[285]
Phenolic acid	Chlorogenic acid	Pimenta dioica	SARS-CoV-2	In vitro	Promising antiviral activity against SARS-CoV-2 (IC₅₀: 360 µg/mL)	[286]
Phenolic acid	Ellagic acid	Rubus fruticosus, Fragaria ananassa	SARS-CoV-2	In vitro	Inhibition of RBD-hACE2 binding (IC₅₀: 2.5 µg/mL).	[287]
Phenylethanoid glycoside	Forsythoside A	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 3.18 µM).	[172]
Phenylethanoid glycoside	Forsythoside B	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 2.88 µM).	[172]
Phenylethanoid glycoside	Forsythoside E	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 6.88 µM).	[172]
Phenylethanoid glycoside	Forsythoside H	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 10.17 µM).	[172]
Phenylethanoid glycoside	Forsythoside I	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 5.47 µM).	[172]
Phenylethanoid glycoside	Isoforsythiaside	Forsythia suspensa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 5.85 µM).	[172]
Phenylethanoid glycoside	Acteoside	Scrophularia ningpoensis, Byblis liniflora	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 43 nM).	[269]
Gingerols	6-Gingerol	Zingiber officinale	SARS-CoV-2	In silico In vitro	Favorable binding affinity with viral proteases (Mpro with − 15.7591 kJ/mol), RNA binding protein and S protein; Reduction of viral titers (EC₅₀: 1.38 µM).	[268], [288]
Phenolic compounds	Stilbenoid	Kobophenol A	Caragana chamlagu, Caragana sinica, Carex folliculata	SARS CoV-2	In vitro	Inhibition of S protein (IC₅₀: 1.81 µM).	[289]
Stilbenoid	Resveratrol	Polygonum cuspidatum	SARS-CoV-2	In vitro	Reduction of the expression of ACE2, the control of the renin-angiotensin system (RAS), the activation of the immune system, and the production of pro-inflammatory cytokines; Potential inhibitory activity against RdRp and PLpro of SARS-CoV-2; Interfering with the virusʼs infectious cycle of reproduction; Reduction of SARS-CoV-2 replication in Vero-E6 cells, as well as in a primary human bronchial epithelial cell type.	[290], [291], [292]
Stilbenoid	Pterostilbene	Vaccinium spp., Pterocarpus marsupium	SARS-CoV-2	In vitro	Reduction of viral titers in Vero E6 (EC₅₀: 19 µM); Inhibition of infection in human primary bronchial epithelial cells.	[292]
Anthraquinone	Aloe emodin	Aloe barbadensis	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 132.00 µM).	[247]
Dianthrone	Sennoside B	Cassia fistula	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 104 nM).	[269]
Naphthodianthrone	Hypericin	Hypericum perforatum	SARS-CoV-2	In vitro	Reduction of SARS-CoV-2 replication in Vero-E6 cells, as well as in a primary human bronchial epithelial cell type. Inhibition of Mpro (IC₅₀: 63.6 µM); Inhibition of PLpro deubiquitinase activity.	[272], [293]
Terpenoids	Monoterpenoid phenol	Carvacrol	Thymus vulgaris	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (− 4.0 kcal/Mol).	[94]
	Sesquiterpene glycoside	Tinocordiside	Tinospora cordifolia	SARS-CoV-2	In silico In vitro	Favorable binding affinity exhibition toward Mpro (8.10 kcal/mol).	[242]
	Sesquiterpene lactone	Arteannuin B	Artemisia annua	SARS-CoV-2	In vitro	Inhibition of Mpro (EC₅₀: 10.28 ± 1.12 µM).	[294], [295]
	Sesquiterpene lactone	Artemisinin	Artemisia annua	SARS-CoV-2	In silico In vitro	Inhibition of Mpro (IC₅₀: 70 µM); Antiviral activity (EC₅₀: 64.45 ± 2.58 µM); Range of EC₅₀ in different cell types: 151 to at least 208 µg/mL; The artemisinin-piperaquine group cleared SARS-CoV-2 faster in mild-to-moderate COVID-19 patients compared to the control group. Nonetheless, physicians should be cautious of QT interval changes when administering artemisinin-piperaquine (an open-label, non-randomized, and controlled trial).	[294], [295], [296], [297], [298], [299]
	Sesquiterpene lactone	Artesunate	Artemisia annua	SARS-CoV-2	In vitro	Antiviral activity (EC₅₀: 12.98 ± 5.30 µM); Range of EC₅₀ in different cell types: 7 – 12 µg/mL; Inhibition of Mpro.	[294], [295], [297]
	Sesquiterpene lactone	Artelinic acid	Artemisia annua	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward S protein (− 7.1 kcal/mol) and Mpro.	[295], [299]
	Sesquiterpenoid	Ichangin	Citrus cavaleriei, Citrus medica, Raputiarana heptaphylla	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (− 8.40 kcal/Mol).	[216]
	Diterpenoid	Ferruginol	Torreya nucifera	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 49.6 ± 1.5 µM) dose-dependently.	[275]
	Diterpenoid	Dihydrotanshinone I	Salvia miltiorrhiza	SARS-CoV-2 SARS-CoV	In vitro In vivo	Inhibition of SARS-CoV-2 PLpro (IC₅₀: 0.5861 µM); Inhibition of Mpro (EC₅₀: 14.40 µM) and PLpro (EC₅₀: 4.90 µM) of SARS-CoV.	[217], [300]
Terpenoids	Diterpenoid	Rosmariquinone	Salvia miltiorrhiza	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 21.10 µM); Inhibition of PLpro (IC₅₀: 30.00 µM).	[217]
Diterpenoid	Tanshinone I	Salvia miltiorrhiza	SARS-CoV-2 SARS-CoV	In vitro	Reduction of viral titers (EC₅₀: 2.26 µM); Inhibition of SARS-CoV-2 PLpro (IC₅₀: 5.63 µM); Inhibition of Mpro (EC₅₀: 38.70 µM) and PLpro (EC₅₀: 8.80 µM) of SARS-CoV.	[217], [301]
Diterpenoid	Tanshinone II	Salvia miltiorrhiza	SARS-CoV-2	In vitro	Inhibition of PLpro (IC₅₀: 1.571 µM).	[217]
Diterpenoid	Andrographolide	Andrographis paniculata	SARS-CoV-2	In vitro	Reduction of viral titers in Calu-3 cell line and Vero E6 cells (EC₅₀: 0.034 µM and 0.28 µM resp.); Inhibition of Mpro (IC₅₀: 15.05 µM).	[302], [303]
Triterpenoid	Ursolic acid	Vaccinium spp., Ocimum sanctum	SARS-CoV-2	In silico In vitro	Inhibition of Mpro (IC₅₀: 12.57 µM); Favorable binding affinity exhibition toward Mpro (8.52 kcal/mol); Favorable binding affinity exhibition toward Mpro (− 5.9 kcal/mol).	[94], [242], [304]
Triterpenoid	Betulinic acid	Betula pubescens, Ziziphus mauritiana, Breynia fruticosa	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 14.55 µM); Inhibition of SARS-CoV-2 S protein RBD binding to ACE2 of host cell (IC₅₀: 0.1 µM).	[210], [304]
Triterpenoid	Oleanolic acid	Betula pubescens, Ziziphus mauritiana, Breynia fruticosa	SARS-CoV-2	In silico In vitro	Favorable binding affinity exhibition toward Mpro (− 6.0 kcal/mol); Inhibition of SARS-CoV-2 S protein RBD binding to ACE2 of host cell (IC₅₀: 1 µM).	[94], [210]
Triterpenoid	Betulin	Betula pubescens, Ziziphus mauritiana	SARS-CoV-2	In vitro	Inhibition of Mpro (IC₅₀: 89.67 µM).	[304]
Triterpenoid	Glycyrrhetinic acid	Glycyrrhiza glabra	SARS-CoV-2	In vitro	Inhibition of S protein-ACE2 binding between SARS-CoV-2 and host cell (IC₅₀: 10 µM).	[210]
Triterpenoid	Maslinic acid	Olea europaea	SARS-CoV-2	In vitro	Inhibition of Mpro through a protease assay (IC₅₀: 3.22 µM).	[304]
Triterpenoid	β-Amyrin	Pisum sativum Brassica oleracea Celastrus hindsii	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (− 8.79 kcal/Mol).	[216]
Triterpenoid	Iguesterin	Tripterygium regelii	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 2.6 ± 0.3 µM).	[305]
Triterpenoid	Celastrol	Tripterygium regelii	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 10.3 ± 0.2 µM).	[305]
Triterpenoid	Pristimerin	Tripterygium regelii	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 5.5 ± 0.7 µM).	[305]
Triterpenoid	Tingenone	Tripterygium regelii	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 9.9 µM).	[305]
Triterpenoid (limonoid)	Deacetylnomilin	Citrus spp.	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (− 8.35 kcal/Mol).	[216]
Triterpenoid (saponin)	Glycyrrhizin	Glycyrrhiza glabra	SARS-CoV-2	In silico In vitro	Reduction of viral titers (EC₅₀: 0.44 mg/ml); Dose-dependent inhibition of Mpro.	[306], [307]
Terpenoids	Triterpenoid (saponin)	Saikosaponins U and V	Bupleurum spp., Heteromorpha spp., Scrophularia scorodonia	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward S protein (− 7.272 and − 8.358 Kcal/Mol respectively).	[308]
Triterpenoid (saponin)	Platycodin D	Platycodon grandiflorus	SARS-CoV-2	In vitro	Limiting the SARS-CoV-2 pseudotyped virus entrance into H1299/ACE2 (EC₅₀: 0.69 µM) and H1299/ACE2-TMPRSS2 cells (EC₅₀: 0.72 µM).	[309]
Steroidal sapogenin	Sarsasapogenin	Anemarrhena asphodeloides	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward non-structural protein 15 (− 8.5 kcal/Mol).	[310]
Cardiac glycoside	Ouabain	Acokanthera schimperi, Strophanthus Gratus, Breynia fruticosa	SARS-CoV-2	In vitro	Reduction of viral RNA when added pre-infection and post-entry (IC₅₀: 0.024 µM).	[311]
Cardiac glycoside	Digoxin	Digitalis lanata	SARS-CoV-2	In vitro	Reduction of viral RNA when added pre-infection and post-entry (EC₅₀: 0.043 µM).	[311]
Withanolide glycoside	Withanoside V	Withania somnifera	SARS-CoV-2	In silico	Favorable binding affinity exhibition toward Mpro (IC₅₀: 10.32 kcal/mol).	[242]
Miscellaneous compounds	Cinnamic amide	Terrestriamide	Tribulus terrestris, Ocimum sanctum	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 21.50 µM).	[312]
	Cinnamic amide	N-trans-caffeoyltyramine	Tribulus terrestris	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 44.40 µM)	[312]
	Cinnamic amide	N-trans-coumaroyltyramine	Tribulus terrestris	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 38.80 µM).	[312]
	Cinnamic amide	N-trans-feruloyloctopamine	Tribulus terrestris	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 26.60 µM).	[312]
	Cinnamic amide	N-trans-feruloyltyramine	Tribulus terrestris	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 70.10 µM).	[312]
	Cinnamic amide	Terrestrimine	Tribulus terrestris	SARS-CoV	In vitro	Inhibition of PLpro (IC₅₀: 15.80 µM).	[312]
	Glucosinolate	Sinigrin	Isatis indigotica	SARS-CoV	In vitro	Inhibition of Mpro (IC₅₀: 121.00 µM).	[247]
	Lectin	Griffithsin	Griffithsia capitata	SARS-CoV	In vitro In vivo	Antiviral activity (EC₅₀:48 – 94 nM); Inhibition of SARS-CoV S protein; Reduction of SARS-CoV infectivity in vivo (mouse-adapted SARS-CoV) and in vitro investigations; Recombinant griffithsin exhibited IC₅₀ values of 34.0 and 5.4 nM against Delta and Omicron variants, respectively; Q-Griffithsin, when combined with carrageenan, exhibited a synergistic effect (EC₅₀: 0.2 – 3.8 µg/mL), and the combination index was less than 1, indicating a strong synergistic effect; Inhibition of SARS-CoV-2 pseudovirus infection (IC₅₀: 63 nmol/L); Inhibition of SARS-CoV-2 S-mediated cell to cell fusion (IC₅₀: 323 nmol/L).	[313], [314], [315], [316]

Until now, the evaluation of the in vivo antiviral effects of plants in animal models infected with SARS-CoV-2 has primarily relied on crude extracts. Deng et al. conducted a study to evaluate the effectiveness of Pudilan Xiaoyan Oral Liquid (PDL), a traditional Chinese medicine containing Isatis indigotica, Corydalis bungeana, Taraxacum mongolicum, and Scutellaria baicalensis [105]. The researchers examined the potential of PDL against SARS-CoV-2 through in vitro and in vivo studies [105]. Their findings, combined with bioinformatics and network pharmacology analyses, demonstrated that PDL exhibited strong antiviral activity against SARS-CoV-2 and showed promising results both in vitro and in vivo [105]. These results suggest that PDL could be considered for clinical use as a treatment for pneumonia caused by SARS-CoV-2 infection, either alone or in combination with other effective antiviral medications [105].

To advance phytochemicals into antiviral drugs for the treatment of COVID-19, more comprehensive experimental and preclinical investigations, including bioavailability, pharmacokinetics, pharmacodynamics, and toxicological studies, must be conducted in animal models. These essential steps are required before the compounds can be considered for human studies.

For instance, baicalein, a compound from Scutellaria baicalensis, was studied by Song et al. for its therapeutic effects on COVID-19 [106]. The research showed that baicalein protected cells from SARS-CoV-2 damage and improved their morphology [106]. Oral administration of baicalein reached effective concentrations, inhibiting virus replication and reducing lung tissue damage in infected mice [106]. In addition, baicalein improved respiratory function and decreased inflammation in mice with lung injury [106]. These findings suggest baicalein as a promising treatment for COVID-19.

The bioavailability and solubility challenges associated with utilizing plant secondary metabolites for antiviral administration in drug discovery and development can be overcome through the utilization of drug delivery systems. Encapsulating or linking these compounds with nanocarriers provides a promising solution to enhance their delivery, distribution, degradation, and availability [107]. Organic-based nanocarriers, such as micelles, liposomes, niosomes, bilosomes, solid lipid nanoparticles, and archaeosomes, are commonly employed for transporting hydrophobic drugs within the body [108]. Furthermore, various pharmaceutical formulations and delivery systems, including nanosuspensions, solid dispersions, microspheres, crystals, self-nanoemulsifying drug delivery systems (SNEDDS), and self-microemulsifying drug delivery systems (SMEDDS), have been developed and utilized to deliver natural products with antiviral properties [109]. These diverse technologies offer effective and reliable delivery of medicinal phytochemicals, addressing the challenges of bioavailability and solubility in antiviral drug administration.

A number of plant secondary metabolites have been subjected to clinical trials, with some trial outcomes still pending publication. These trials assess the efficacy of phytochemicals as standalone compounds, in combination with other natural bioactive compounds, drugs, or polyphenol-rich extracts and are specifically enumerated in [Table 3]. The list is sourced from ClinicalTrials.gov (accessed on June 20, 2023). As previously mentioned, numerous plant secondary metabolites have demonstrated favorable results in in silico, in vitro, and in vivo studies. Considering this, there is an optimistic outlook for the continuation of further clinical trials on these promising plant secondary metabolites.

Table 3 List of promising SMs undergoing clinical trials as of June 20, 2023. Retrieved from www.clinicaltrials.gov.
SM	Official title of the clinical trial	Intervention/treatment	Results	ClinicalTrials.gov identifier	References
Q-Griffithsin	A phase 1a safety, acceptability and pharmacokinetics study of Q-griffithsin intranasal spray for broad-spectrum coronavirus pre- exposure prophylaxis: a study of the prevent-COVID-19 program	Drug: Q-Griffithsin intranasal spray administered as a single dose	Not posted yet	NCT05122260	–
Ferulic acid	Retrospective observational study to describe the evolution of SARS-CoV-2 disease and the profile of patients treated or not with Imuno TF and a combination of nutraceuticals and who have tested positive for COVID-19	Dietary supplement: ImmunoFormulation (ImmunoFormulation contains Imuno TF, selenium, zinc, ascorbic acid, vitamin D, Miodesin, resveratrol, Spirulina, ferulic acid, glucosamine, N-acetylcysteine, and SiliciuMax.)	Not posted yet	NCT04666753	–
Luteolin	Effects of palmitoylethanolamide co- ultramicronized with luteoline (Pea-lut) on frontal lobe functions and GABAergic transmission in long COVID patients. An 8-week randomized controlled trial	Dietary supplement: palmitoylethanolamide co-ultramicronized with antioxidant flavonoid luteolin (PEA-LUT)	Not posted yet	NCT05311852	–
Luteolin	Olfactory dysfunction after COVID-19: conventional therapy versus intervention treatment with co-ultraPEALut	Combination product: co-ultraPEALut	Not posted yet	NCT04853836	–
Quercetin	A prospective, randomized, open-labelled, controlled trial to study the adjuvant benefits of Quercetin Phytosome in patients with diagnosis of COVID-19	Drug: Standard COVID-19 care Dietary supplement: Quercetin Phytosome	The supplementation demonstrated notable reductions in the hospitalization rate (9.2% vs. 28.9%), length of hospital stay (1.6 vs. 6.8 days), need for oxygen therapy (1.3 vs. 19.7%), and symptom severity when compared to the control group.	NCT04578158	[317]
	Study to investigate the benefits of dietary supplement quercetin for early symptoms of COVID-19	Drug: standard of care for COVID-19 as per the hospital guidelines Dietary supplement: Quercetin Phytosome (QP)	The results indicated that quercetin not only expedited the conversion of positive molecular test results to negative but also alleviated the severity of COVID-19 symptoms. The number of patients hospitalized was lower than in the control group.	NCT04861298	[318], [319]
	The study of quadruple therapy zinc, quercetin, bromelain and vitamin C on the clinical outcomes of patients infected with COVID-19	Drug: quercetin Dietary supplement: bromelain Drug: Zinc Drug: vitamin C	Not posted yet	NCT04468139	–
	Treatment benefits of flavonoids quercetin and curcumin supplements for mild symptoms of COVID-19	Drug: standard of care Dietary supplement: investigational treatment	Not posted yet	NCT05130671	–
	Randomized, placebo-controlled clinical trial to evaluate the efficacy of an oral nutritional supplement based on quercetin in the prevention of COVID-19 infection for a duration of 3 months	Dietary supplement: quercetin	Not posted yet	NCT05037240	–
	Complementary therapy of dietary supplements curcumin, quercetin and vitamin D3 for mild to moderate symptoms of COVID-19	Dietary supplement: complementary therapy Drug: standard of care	Not posted yet	NCT04603690	–
	Quercetin	The effectiveness of phytotherapy in the treatment of SARS-COV2 (COVID-19)	Drug: quercetin	Not posted yet	NCT04851821	–
	Efficacy of Psidii guavaʼs extract for mild and symptomless coronavirus disease-19 (COVID-19)	Drug: extract Psidii guava Combination product: standard therapy for COVID-19 patient	Not posted yet	NCT04810728	–
	Safety and efficacy of hydroxychloroquine for the treatment & prevention of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)	Drug: hydroxychloroquine Dietary supplement: vitamins and minerals Drug: azithromycin	Not posted yet	NCT04590274	–
	A comparative randomized clinical study on COVID-19 positive hospitalized patients supplemented with NASAFYTOL	Dietary supplement: NASAFYTOL (NASAFYTOL is a dietary supplement that contains a mixture of curcumin, quercetin, and vitamin D.) Dietary supplement: FULTIUM-D3 800 Drug: standard of care treatment	Not posted yet	NCT04844658	–
Epigallocatechin-3-gallate (EGCG)	A multicenter, double-blind, randomized, placebo-controlled clinical trial to protect health workers against COVID-19 by Using Previfenon as chemoprophylaxis during a SARS-CoV-2 outbreak. The HERD study	Drug: Previfenon (EGCG)	Not posted yet	NCT04446065	–
Curcumin	The effect of a mixture of micellized curcumin/Boswellia serrata/ascorbic acid on health-related quality of life in patients with post-acute COVID-19 syndrome	Dietary supplement: curcumin/Boswellia serrata/ascorbic acid mixture	Not posted yet	NCT05150782	–
	Treatment benefits of flavonoids quercetin and curcumin supplements for mild symptoms of COVID-19	Drug: standard of care Dietary supplement: investigational treatment	Not posted yet	NCT05130671	–
	Complementary therapy of dietary supplements curcumin, quercetin and vitamin D3 for mild to moderate symptoms of COVID-19	Dietary supplement: complementary therapy Drug: standard of care	Not posted yet	NCT04603690	–
	A phase III, double-blind, controlled clinical study designed to evaluate the effect of CimetrA in patients diagnosed with COVID-19	Drug: CimetrA-1 (CimetrA-1 contains a combination of curcumin (40 mg), frankincense extract (30 mg), and ascorbic acid (120 mg).) Drug: CimetrA-2 (CimetrA-2 contains a combination of curcumin (28 mg), frankincense extract (21 mg), and ascorbic acid (84 mg).)	Not posted yet	NCT04802382	–
	A phase II, controlled clinical study designed to evaluate the effect of ArtemiC in patients diagnosed with COVID-19	Drug: ArtemiC (ArtemiC contains a combination of artemisinin (12 mg), curcumin (40 mg), frankincense extract (30 mg) and ascorbic acid (120 mg).	Not posted yet	NCT04382040	–
	A Phase II b, double blind, placebo-controlled clinical study designed to evaluate the effect of CimetrA in patients diagnosed with COVID-19	Drug: treatment administration (twice a day)	Not posted yet	NCT05037162	–
	Oral nutritional supplements in treatment of elderly mild-to- moderate COVID-19 (ONSITEMC)	Dietary supplement: oral nutritional supplements	Not posted yet	NCT05629975	–
	Curcumin	A comparative randomized clinical study on COVID-19 positive hospitalized patients supplemented with NASAFYTOL	Dietary supplement: NASAFYTOL (NASAFYTOL is a dietary supplement that contains a mixture of curcumin, quercetin, and vitamin D.) Dietary supplement: FULTIUM -D3 800 Drug: standard of care treatment	Not posted yet	NCT04844658	–
Resveratrol	Randomized double-blind placebo-controlled proof-of- concept trial of resveratrol, a plant polyphenol, for the outpatient treatment of mild coronavirus disease (COVID- 19)	Drug: resveratrol Dietary supplement: vitamin D3	The resveratrol group exhibited a lower incidence of hospitalization, COVID-19-related Accident and emergency visits, and pneumonia when compared to the placebo group	NCT04400890	[320]
	A pilot randomized controlled clinical study of resveratrol for discharged COVID 19 patients in order to evaluate its therapeutic effects against fibrosis	Drug: resveratrol	Not posted yet	NCT04799743	–
	Can SARS-CoV-2 viral shedding in COVID-19 disease be reduced by resveratrol- assisted zinc ingestion, a direct inhibitor of SARS-CoV-2-RNA polymerase? a single blinded phase II protocol (reszinate trial)	Dietary supplement: zinc picolinate Dietary supplement: resveratrol	Not posted yet	NCT04542993	–
	Retrospective observational study to describe the evolution of SARS-CoV-2 disease and the profile of patients treated or not with Imuno TF and a combination of nutraceuticals and who have tested positive for COVID-19	Dietary supplement: ImmunoFormulation (ImmunoFormulation contains Imuno TF, selenium, zinc, ascorbic acid, vitamin D, Miodesin, resveratrol, Spirulina, ferulic acid, glucosamine, N-acetylcysteine, and SiliciuMax.)	Not posted yet	NCT04666753	–
Oleuropein	Assessment of the clinical effectiveness of standardized olive leaf capsules; as a co-therapy in the treatment of non-hospitalized COVID-19 patients; a randomized clinical trial	Dietary supplement: NusaPure standardized olive leaves capsule, 750 mg (50% oleuropein)	Not posted yet	NCT04873349	–
Oleuropein	Evaluation of the immunomodulatory and preventive effects of olive leaf tea against COVID-19	Dietary supplement: olive leaf tea	Not posted yet	NCT05222347	–

#
#

Plant Metabolites and Their Effectiveness in Treatment of COVID-19

Plant compounds can be classified into primary and SMs [52]. Primary metabolites like proteins, lipids, and carbohydrates directly contribute to plant growth and development [52]. SMs, on the other hand, are versatile molecules that are often involved in environmental communication and plant defense [110]. They are also responsible for plant taste, odor, and color [52]. SMs are low-molecular-weight compounds and are biosynthetically derived from primary metabolites but are restricted to specific taxonomic groups or families in the plant kingdom [50], [110]. They are synthesized by specialized cell types at certain developmental stages [111]. SMs are found to have ecological functions, such as attracting pollinators, chemical adaptation to stress, or defense against predators or harmful microorganisms [111], [112].

Medicinal products from plants or herbs account for about 35% of the global medicine market (valued at USD1.1 trillion) [113]. As a source of antiviral chemicals, plant SMs offer a less expensive alternative to conventional medicines [114]. Metabolites of different medicinal plants and their mechanisms in dealing with SARS-CoV-2 and other coronaviruses are summarized in [Table 2].

#

Flavonoids

Flavonoids are SM compounds found in many fruits, seeds, and leaves that act as a defensive mechanism against abiotic stressors [115], [116], [117]. The structure of flavonoids consists of a 15-carbon skeleton composed of two benzene rings joined by a pyran ring [118].

A large number of compounds belonging to this group show significant antiviral effects [119], [120]. Flavonoids have antiviral properties that hinder the virusʼs ability to attach and penetrate cells, impede its growth and transmission, stop the production of viral proteins and coatings formed by glycoprotein complexes [120]. Flavonoids also aid the communication process within the infected cell by activating transcription factors and releasing cytokines [121].

To date, a large number of flavonoids have been identified from various plant species. Based on their chemical structure, degree of oxidation, and substitution pattern of the C ring (heterocyclic pyran ring), they are divided into flavanones, flavonols, flavanols, flavones, isoflavonoids, chalcones, and anthocyanidins [119]. Considering that these compounds have shown potential antiviral properties against coronaviruses, they may also be effective in the treatment of COVID-19 [122].

Silymarin is obtained from the plant source Silybum marianum, native to Crete, Greece, Iran, and Afghanistan, and is a blend of flavonolignans (silybin, isosilybin, silychristin, and siliandrin) and a flavonol (taxifolin) [123]. It is widely recognized for its liver-protective properties [124]. Its anti-SARS-CoV-2 potential stems from its ability to decrease the expression of the host cell surface receptor TMPRSS2 [123]. Hanafy et al. produced bovine serum albumin nanoparticles loaded with silymarin and curcumin to build an inhalable delivery method for pneumonia treatment [125]. They discovered that silymarin has potential antiviral efficacy against SARS-CoV-2 in vitro at a dose of 25 g/mL [125]. According to the findings, silymarinʼs anti-inflammatory and antioxidant properties may protect the lungs during SARS-CoV-2 infection and inhibit the ACE2 receptor, preventing viral entry [125]. Currently, a phase III clinical study (NCT04394208) is recruiting participants to assess the clinical outcomes of silymarin in adults with COVID-19 pneumonia under standard care, with either a placebo or oral silymarin [126].

One of the main concerns with the administration of flavonoids is that they have limited absorption and bioavailability when taken orally due to their hydrophilic nature as glycosides [127], [128]. Flavonoids are extensively metabolized in the intestine and liver, resulting in the formation of conjugated forms that facilitate their elimination [127]. Consequently, the low bioavailability of flavonoids poses a challenge for oral administration [127]. To address this issue, various strategies have been employed, such as using nano-formulations to improve intestinal absorption, employing microemulsions or complexing with β-cyclodextrin to enhance bioavailability [127]. Inhalation of flavonoids encapsulated in smart nanoparticles targeting ACE2 receptors has been shown to increase bioavailability and efficacy in mice [122]. Additionally, nano-emulsion and nano-liposomal formulations have been found to improve oral bioavailability, therapeutic efficacy, and stability of flavonoids like naringenin and fisetin, with the latter exhibiting a 47-fold increase in bioavailability compared to the free form [129], [130].

Here, we focus on the flavonoids quercetin, baicalin, baicalein, kaempferol, luteolin, and a group of flavan-3-ols known as catechins, which have shown promise in COVID-19 drug discovery and development. These compounds have been the subject of numerous studies due to their potential antiviral effects against SARS-CoV-2.

Quercetin

Quercetin is a flavonoid found in vegetables such as onions, dill, and cilantro and fruits such as capers, apples, and berries [131]. Molecular docking and SPR/FRET-based bioassays, as well as mutagenesis studies, indicated the potential antiviral effect of quercetin and its derivatives by inhibiting the Mpro of the SARS-CoV virus [132]. Considering the similarity of more than 95% of the gene encoding Mpro in SARS-CoV-2 with the same gene in the SARS-CoV virus, Mpro inhibitors are considered promising drugs for COVID-19 [114]. Quercetin exhibited more than 80% inhibitory activity on recombinant Mpro expressed in Pichia pastoris yeast in laboratory conditions (with an IC₅₀ value of 73 µM) [133]. Recent computational studies and data from molecular docking also indicated that this molecule is one of the potential inhibitors of the Mpro of the SARS-CoV-2 virus [134], [135], [136].

According to Cherrak et al., quercetin-3-O-rhamnoside and quercetin-3-O-neohesperidoside display a strong inhibitory activity on SARS-CoV-2 Mpro [137]. Surprisingly, it has been shown that quercetin and quercetin-3-O-glucoside form better bonds with PLpro and Mpro viral proteins compared to remdesivir as a positive control [138]. Quercetin-3-O-glucoside had the highest PLpro binding score among the tested molecules [138]. In addition, a computer study conducted by Joshi et al. showed that quercetin-3-O-vicianoside, quercetin-3-O-glucuronide-7-O-glucoside, and quercetin-7-O-galactoside had low binding energy with the Mpro of the SARS-CoV-2 virus [139].

Quercetin and its derivatives show high binding energy with other drug targets such as S protein, ACE2 [140], [141], [142], [143], [144], and RdRp [145], [146]. Ascorbate and quercetin work synergistically to treat COVID-19 due to their shared antiviral and immunomodulatory effects, as well as ascorbateʼs ability to recycle quercetin [147].

Isoquercetin is the 3-O-glucoside of quercetin [148]. It has a higher accumulation rate than quercetin in the intestinal mucosa, where it is converted to quercetin, which is then absorbed by enterocytes, transported to the liver, released into circulation, and distributed to organs, primarily as metabolic conjugates [148]. In general, isoquercetin is less active than quercetin in vitro and ex vivo, but it is equally or more active in vivo, suggesting that it is largely a more absorbable precursor to quercetin, with better pharmacokinetics [148].

However, there are some aspects hampering the utilization of quercetin as a drug, such as its low absorption and bioavailability, quick metabolism, and interindividual variability [149], [150]. Serum albumin sequesters quercetin, contributing to its poor bioavailability [151]. Oral administration of isoquercetin, on the other hand, has much higher bioavailability than quercetin itself [152]. Isoquercetin also has a lower affinity for albumin, suggesting that it is less sequestered in the intestines and blood [151]. It has been shown that quercetin accumulates in red blood cells and may be removed by albumin, indicating that albumin may operate as a quercetin transporter in the body [149], [153]. Furthermore, quercetin metabolites, such as quercetin 3-O-glucuronide and isorhamnetin, have physiological features comparable to the aglycone form, including antiviral capabilities [154], [155], [156].

#

Kaempferol

Kaempferol is another flavonoid that belongs to the flavonol subclass. According to a study conducted by Schwarz et al. in 2013, kaempferol derivatives containing a rhamnose residue demonstrate significant effectiveness in inhibiting the 3a ion channel, a channel crucial to the intricate release mechanism of SARS-CoV [157]. The researchers propose that viral ion channels, in general, hold promise as targets for developing antiviral agents [157]. Specifically, they highlight kaempferol glycosides as strong candidates for targeting the 3a channel proteins of coronaviruses [157]. Moreover, in a study conducted by Shaldam et al. in 2021, it was found that kaempferol exhibits one of the strongest interactions with the target enzymes of SARS-CoV-2, namely Mpro and RdRp [158]. As a result, it may be considered an effective inhibitor for SARS-CoV-2 [158].

#

Catechins

Catechins and their derivatives, including (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechingallate (ECG), and (−)-epigallocatechin (EGC), belong to the subclass of flavanols and have many medicinal properties [159]. Considering the ability of catechins to bind to the viral S protein and ACE2 of the host cell, they can be considered as an option for treating COVID-19 [160].

In a study conducted by Henss et al. among the different catechins, EGCG was particularly effective in inhibiting the SARS-CoV-2 virus and showed no toxicity at effective concentrations [161]. EGCG also prevented SARS-CoV-2 from binding to ACE2 when used before COVID-19 infection [161]. EGCG was found to reduce virus infections in vitro by preventing the entry of SARS-CoV-2, as well as MERS-CoV and SARS-CoV pseudo-typed lentiviral vectors, indicating a more general antiviral effect of this compound [161]. In contrast, epicatechin (EC) did not show any effect in inhibiting SARS-CoV-2 and other coronaviruses [161]. In one study, catechin performed better than six conventional drugs, namely tenofovir, ritonavir, dolutegravir, boceprevir, tinofoviralafenamide, and zanamivir, in serving as a multi-target drug because it exhibits the highest binding strength to the five proteins that the virus requires to infiltrate the host cell, namely the receptor-binding domain (RBD), cathepsin L, N protein, Mpro, and nonstructural protein 6 [162]. In a separate study, all types of catechins, including ECGC, indicated a considerable affinity to the S protein of the SARS-CoV-2 virus [163]. Moreover, Rabezanahary et al. demonstrated the inhibitory effects of EGCG and isoquercetin against SARS-CoV-2 in vitro and proved their substantial antiviral synergistic effects with remdesivir [164].

It is important to note that a clinical phase II/III trial is currently underway (NCT04446065) to evaluate the chemoprophylactic effects of EGCG on COVID-19 in healthy workers [165].

#

Baicalin and baicalein

Baicalin and baicalein are two compounds that are primarily obtained from the root of Scutellaria baicalensis, an East Asian plant [166]. In traditional Chinese medicine, this plant is used to treat obesity, hypertension, and dysentery, as well as inflammatory diseases, arteriosclerosis, and the common cold [167], [168].

When baicalin is metabolized in the intestine, it transforms into baicalein [169]. Numerous studies have reported that both of these compounds have an inhibitory effect against the SARS-COV-2 virus, particularly 3CLpro [170], [171], [172], [173].

Zandi et al. have demonstrated that baicalein and its aglycon baicalein exhibit in vitro anti-SARS-CoV-2 activity, directly inhibiting the activity of SARS-CoV-2 RdRp [169]. They reported an EC₅₀ of 4.5 µM and an EC₉₀ of 7.6 µM for baicalein [169]. Su et al. found the binding activity of baicalein with Mpro and confirmed its anti-SARS-CoV-2 activity in vitro [172]. Moreover, their further study highlighted the presence of baicalin and baicalein, two bioactive ingredients of Shuanghuanglian (a Chinese traditional medicine), which provided supporting evidence for the potential antiviral activity of Shuanghuanglian [172]. However, the exact antiviral ability of baicalin and baicalein requires verification through animal models or clinical trials.

#

Luteolin

Luteolin is a flavonoid present in edible plants, including oregano, celery, parsley, and juniper berries [174]. Investigations into the properties of luteolin against the SARS-CoV virus have demonstrated its antiviral nature [175], [176]. Its potential in preventing the entry of SARS-CoV-2 into cells has been supported by various analyses, including the relaxed complex scheme analysis, classical molecular docking simulations, and metadynamics simulations [177]. Researchers such as Xie et al. conducted a comprehensive study employing system pharmacology and bioinformatic analysis, which revealed that luteolin holds significant promise as a treatment for COVID-19/asthma comorbidity [178]. This is attributed to its antiviral effects, regulation of inflammation and immune responses, reduction in oxidative stress, and modulation of blood circulation [178]. Clinical findings further suggest that oral supplementation of luteolin improves the recovery of olfactory function following COVID-19 [179].

Recent studies showed the significant inhibitory activity of luteolin against the Mpro of SARS-CoV-2, papainlike proteinase. In addition, luteolin prevents the coronavirus from binding to human cell receptors and entering the cells [180], [181].

#
#

Alkaloids

Alkaloids are a large group of natural compounds that contain at least one nitrogen atom, often located in a heterocyclic ring [182].

Alkaloids are abundant in the human diet [183]. Edible plants such as coffee, cocoa, tea, tomatoes, and potatoes contain alkaloid compounds [183]. In previous studies on the inhibitory effect of plant metabolites on the SARS-CoV virus, alkaloids such as berberrubine, berberine, berbamine, dicentrine, coptisine jatrorrhizine, palmatine, tetrandrine, fangchinoline, and cepharanthine have been reported as inhibitors of SARS-CoV proliferation [184], [185], [186], [187]. Lycorine, found in the Amaryllidaceae family, also has a potential antiviral effect against SARS-CoV [188].

Schizanthine z is an alkaloid obtained from Schizanthus porrigens. This compound has an inhibitory effect against the PLpro of SARS-CoV-2 [189]. Cryptoquindoline and cryptospirolepine, two alkaloids from Cryptolepis sanguinolenta, showed an inhibitory effect against the Mpro of SARS-CoV-2 [190]. Other alkaloids that have an inhibitory effect against the Mpro of this virus are anisotine, adhatodine, vasicoline, and vasicine, which are found in the Justicia adhatoda plant [191]. In addition, an in silico investigation found that thalimonine and sophaline D may have antiviral activity against SARS-CoV-2 Mpro [192]. A number of alkaloids also showed an inhibitory activity against the RdRp of SARS-CoV-2 including several compounds from Cryptolepis sanguinolenta including cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine [190].

Colchicine

Colchicine, one of the oldest anti-inflammatory medications, is a tropolone alkaloid derived from the plants Colchicum autumnale and Gloriosa superba [193]. Colchicine gained approval from the US FDA in 2009 for treating familial Mediterranean fever (FMF) and preventing and managing gout attacks [194]. According to a study by Karatza et al., colchicine is a promising drug for COVID-19 patients [193]. Through their research, various dosage regimens were explored, with the findings indicating that a safe and effective approach involves a dosage of 0.5 mg administered twice daily [193]. For patients with clearance impairment, lower doses of 0.25 mg twice or thrice daily should be used [193]. It is important to design dosage regimens based on individual patient needs since colchicine has a narrow therapeutic index [193].

Colchicine can indirectly obstruct the NLRP3 inflammasome, a large molecular complex responsible for detecting danger and initiating a localized or systemic inflammatory response by releasing pro-inflammatory cytokines, such as IL-1β [195], [196], [197]. Moreover, colchicine disrupts various inflammatory processes such as the movement, attachment, and activation of neutrophils, as well as the triggering of inflammasomes and the release of cytokines [198]. Considering the impact of colchicine on reducing the activity of various inflammatory pathways and its ability to adjust innate immunity, it is plausible to consider it as a potential treatment for COVID-19 [198]. This is particularly relevant because the autoinflammation of both the innate and adaptive immune systems is a distinguishing feature of the COVID-19 disease [198].

Notably, colchicine has been examined in both outpatient and inpatient settings for its effectiveness against COVID-19 [199], [200], [201], [202], [203], [204], [205], [206], [207].

#
#

Terpenoids

Terpenoids are the most abundant and diverse class of naturally occurring phytoconstituents [208]. They are responsible for the scent, flavor, and coloration of plants [208]. Their categorization is determined by the number of isoprene units (C₅H₈), which serve as the building blocks of terpenoids [208].

In a computational investigation, numerous components from essential oils, such as cinnamaldehyde, carvacrol, cinnamyl acetate, anethole, pulegone, and thymol, have been identified as obstructing the SARS-CoV-2 virus S protein [209]. In a study by Carino et al., betulinic and oleanolic acids were reported to reduce the binding of S protein RBD to the ACE2 receptor in a concentration-dependent manner [210]. An in silico study found that 3-oxoglycyrrhetinic acid inhibited SARS-CoV-2 Mpro [211].

The effect of bioactive molecules from Withania somnifera or “Indian ginseng” on the Mpro of SARS-CoV-2 indicated that the steroid compound withanoside V has the highest inhibitory effect on this viral protease among the molecules studied [212]. Other compounds from this plant, including quercetin-3-O-galactosyl-rhamnosyl-glucoside, withanoside X, ashwagandhanolide, dihydrowithaferin A, and withanolide N, showed a promising inhibitory effect on S glycoprotein and nonstructural protein 15 endoribonuclease of SARS-CoV-2 [213].

Recent in silico analysis showed the substantial affinity of terpenoids from Nigella sativa, including campesterol, cycloeucalenol, α-spinasterol, and β-sitosterol, for the viral N-terminal RNA-binding domain (NRBD) and PLpro of the SARS-CoV-2 virus [214]. Furthermore, The inhibitory activity of bioactive terpenes against SARS-CoV-2 proteins was investigated in another in silico study [215]. Based on the results, methyl tanshinonate, sugiol, and cadinol are potential SARS-CoV-2 Mpro inhibitors, and 8-hydroxyabieta-9,13-dien-12-one, dehydroabieta-7-one, and tanshinone I show promise as SARS-CoV-2 PLpro inhibitors [215]. Deacetylnomilin, ichangin, nomilin, and β-amyrin have a high binding affinity with the Mpro of SARS-CoV-2 [216]. Deacetylnomilin and ichangin, in particular, can interact directly with the catalytic dyad parts of Mpro [216].

Tanshinones, a class of terpene, have previously been found to have antiviral properties by inhibiting PLpro SARS-CoV-1 [217].

Saponins

Saponins are triterpenoid or steroidal glycosides with a wide range of medicinal effects, including anti-inflammatory, antiviral, and antifungal effects [218]. Due to the stimulation of the mammalian immune system, they are also considered as potential adjuvant vaccines [219], [220].

Glycyrrhizin obtained from the root of Glycyrrhizae radix is a saponin that has shown inhibitory effects against SARS-CoV [221]. This compound shows affinity with the ACE2 receptor of the cell, which is one of the drug targets of SARS-CoV-2 [222].

#
#

Tannins

Tannins are a group of large polyphenolic compounds consisting either of several flavan-3-ol units (known as proanthocyanidins) or of a sugar moiety esterified to a number of organic acids, typically gallic acid or ellagic acid (referred to as hydrolyzable tannins). They have many therapeutic properties, among which are antiviral properties [223]. Based on an in silico study conducted on 19 different tannins, three compounds, pedunculagin, tercatain, and castalin, showed a significant interaction with the catalytic dyad part (Cys145 and His41) of the Mpro of the SARS-CoV-2 virus [224]. According to the results of a recent study, tannic acid also has a significant inhibitory effect on the Mpro and TMPRSS2 of the virus [225].

#

Conclusion

The global healthcare landscape has undergone a significant transformation since the onset of the SARS-CoV-2 outbreak. While COVID-19 once posed a dire and widespread threat to human lives worldwide, the situation has evolved. Thanks to extensive research and the collective efforts of the scientific community and healthcare systems, the pandemic phase of COVID-19 has transitioned into a more manageable state. Despite the progress made, it is essential to acknowledge that only limited options are available for the treatment of COVID-19. Nevertheless, the development of antiviral drugs has expanded the arsenal of available therapeutic choices, and mortality rates, once on the rise, have stabilized. In this new phase, it is crucial to continue exploring therapeutic and preventative measures. Natural resources including plant SMs containing an antiviral agent have the potential to be used to develop medicinal targets and be considered as an efficient alternative for chemical drugs.

This comprehensive review has consolidated the latest investigations employing a triad of methodologies, in vitro, in vivo, and in silico, aimed at identifying prospective plantsʼ secondary metabolites to combat SARS-CoV-2. Our inclusion of agents targeting both anti-SARS-CoV and anti-MERS-CoV was due to the striking similarity between these viruses and SARS-CoV-2. Hopefully, this compilation will facilitate forthcoming laboratory research in the pursuit of novel therapeutics against SARS-CoV-2.

#

Contributorsʼ Statement

Data collection: Z. Alipour, S. Zarezadeh, A. A. Ghotbi-Ravandi; design of the study: Z. Alipour, S. Zarezadeh, A. A. Ghotbi-Ravandi; analysis and interpretation of the data: Z. Alipour, S. Zarezadeh, A. A. Ghotbi-Ravandi; drafting the manuscript: Z. Alipour, S. Zarezadeh; critical revision of the manuscript: A. A. Ghotbi-Ravandi.

#
#

Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgements

We would like to thank Dr. Alireza Majd for his helpful comments.

References
1 COVID-19 statistics. Accessed 03.01.2023 at: https://www.worldometers.info/coronavirus

PubMed Google Scholar
2 Yang H, Bartlam M, Rao Z. Drug design targeting the main protease, the Achillesʼ heel of coronaviruses. Curr Pharm Des 2006; 12: 4573-4590 DOI: 10.2174/138161206779010369.

Crossref PubMed Google Scholar
3 Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect 2021; 54: 159-163 DOI: 10.1016/j.jmii.2020.03.022.

Crossref PubMed Google Scholar
4 Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11: 1620 DOI: 10.1038/s41467-020-15562-9.

Crossref PubMed Google Scholar
5 Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020; 176: 104742 DOI: 10.1016/j.antiviral.2020.104742.

Crossref PubMed Google Scholar
6 Liang Y, Wang ML, Chien CS, Yarmishyn AA, Yang YP, Lai WY, Luo YH, Lin YT, Chen YJ, Chang PC, Chiou SH. Highlight of immune pathogenic response and hematopathologic effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 infection. Front Immunol 2020; 11: 1022 DOI: 10.3389/fimmu.2020.01022.

Crossref PubMed Google Scholar
7 Chen B, Tian EK, He B, Tian L, Han R, Wang S, Xiang Q, Zhang S, El Arnaout T, Cheng W. Overview of lethal human coronaviruses. Signal Transduct Target Ther 2020; 5: 89 DOI: 10.1038/s41392-020-0190-2.

Crossref PubMed Google Scholar
8 Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, Wang Y, Guo X. Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020; 12: 244 DOI: 10.3390/v12020244.

Crossref PubMed Google Scholar
9 Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6: 14 DOI: 10.1038/s41421-020-0153-3.

Crossref PubMed Google Scholar
10 Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends 2020; 14: 69-71 DOI: 10.5582/bst.2020.01020.

Crossref PubMed Google Scholar
11 Cyranoski D. This scientist hopes to test coronavirus drugs on animals in locked-down Wuhan. Nature 2020; 577: 607 DOI: 10.1038/d41586-020-00190-6.

Crossref PubMed Google Scholar
12 Cohen J. New coronavirus threat galvanizes scientists. Science 2020; 367: 492-493

Crossref PubMed Google Scholar
13 Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: Progress and lessons learned. Nat Rev Drug Discov 2023; 22: 449-475 DOI: 10.1038/s41573-023-00672-y.

Crossref PubMed Google Scholar
14 Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 2021; 19: 685-700 DOI: 10.1038/s41579-021-00630-8.

Crossref PubMed Google Scholar
15 Chen Z, Du R, Galvan Achi JM, Rong L, Cui Q. SARS-CoV-2 cell entry and targeted antiviral development. Acta Pharm Sin B 2021; 11: 3879-3888 DOI: 10.1016/j.apsb.2021.05.007.

Crossref PubMed Google Scholar
16 Muralidar S, Gopal G, Visaga Ambi S. Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19. J Med Virol 2021; 93: 5260-5276 DOI: 10.1002/jmv.27019.

Crossref PubMed Google Scholar
17 Tharappel AM, Samrat SK, Li Z, Li H. Targeting crucial host factors of SARS-CoV-2. ACS Infect Dis 2020; 6: 2844-2865 DOI: 10.1021/acsinfecdis.0c00456.

Crossref PubMed Google Scholar
18 Sacco MD, Ma C, Lagarias P, Gao A, Townsend JA, Meng X, Dube P, Zhang X, Hu Y, Kitamura N, Hurst B, Tarbet B, Marty MT, Kolocouris A, Xiang Y, Chen Y, Wang J. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L. Sci Adv 2020; 6: eabe0751 DOI: 10.1126/sciadv.abe0751.

Crossref PubMed Google Scholar
19 Anirudhan V, Lee H, Cheng H, Cooper L, Rong L. Targeting SARS-CoV-2 viral proteases as a therapeutic strategy to treat COVID-19. J Med Virol 2021; 93: 2722-2734 DOI: 10.1002/jmv.26814.

Crossref PubMed Google Scholar
20 Xia Z, Sacco MD, Ma C, Townsend JA, Kitamura N, Hu Y, Ba M, Szeto T, Zhang X, Meng X, Zhang F, Xiang Y, Marty MT, Chen Y, Wang J. Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay. ACS Cent Sci 2021; 7: 1245-1260 DOI: 10.1021/acscentsci.1c00519.

Crossref PubMed Google Scholar
21 Wang Y, Anirudhan V, Du R, Cui Q, Rong L. RNA-dependent RNA polymerase of SARS-CoV-2 as a therapeutic target. J Med Virol 2021; 93: 300-310 DOI: 10.1002/jmv.26264.

Crossref PubMed Google Scholar
22 Niknam Z, Jafari A, Golchin A, Danesh Pouya F, Nemati M, Rezaei-Tavirani M, Rasmi Y. Potential therapeutic options for COVID-19: An update on current evidence. Eur J Med Res 2022; 27: 1-15 DOI: 10.1186/s40001-021-00626-3.

Crossref PubMed Google Scholar
23 Norrie JD. Remdesivir for COVID-19: challenges of underpowered studies. Lancet 2020; 395: 1525-1527 DOI: 10.1016/S0140-6736(20)31023-0.

Crossref PubMed Google Scholar
24 Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev 2023; (01) CD014962 DOI: 10.1002/14651858.CD014962.pub2.

Crossref PubMed Google Scholar
25 Tasavon Gholamhoseini M, Yazdi-Feyzabadi V, Goudarzi R, Mehrolhassani MH. Safety and efficacy of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis. J Pharm Pharm Sci 2021; 24: 237-245 DOI: 10.18433/jpps31870.

Crossref PubMed Google Scholar
26 Patel TK, Patel PB, Barvaliya M, Saurabh MK, Bhalla HL, Khosla PP. Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials. J Infect Public Health 2021; 14: 740-748 DOI: 10.1016/j.jiph.2021.03.015.

Crossref PubMed Google Scholar
27 Samaee H, Mohsenzadegan M, Ala S, Maroufi SS, Moradimajd P. Tocilizumab for treatment patients with COVID-19: recommended medication for novel disease. Int Immunopharmacol 2020; 89: 107018 DOI: 10.1016/j.intimp.2020.107018.

Crossref PubMed Google Scholar
28 Almeida PRL, Person OC, Puga MEDS, Giusti MF, Pinto ACPN, Rocha AP, Atallah ÁN. Effectiveness and safety of tocilizumab for COVID-19: A systematic review and meta-analysis of randomized clinical trials. Sao Paulo Med J 2022; 141: 168-176 DOI: 10.1590/1516-3180.2022.0170.R1.01072022.

Crossref PubMed Google Scholar
29 Sarhan NM, Warda AEA, Ibrahim HSG, Schaalan MF, Fathy SM. Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome. Sci Rep 2023; 13: 6456 DOI: 10.1038/s41598-023-33484-6.

Crossref PubMed Google Scholar
30 Richardson PJ, Robinson BWS, Smith DP, Stebbing J. The AI-assisted identification and clinical efficacy of baricitinib in the treatment of COVID-19. Vaccines 2022; 10: 951 DOI: 10.3390/vaccines10060951.

Crossref PubMed Google Scholar
31 Jorgensen SCJ, Tse CLY, Burry L, Dresser LD. Baricitinib: A review of pharmacology, safety, and emerging clinical experience in COVID-19. Pharmacotherapy 2020; 40: 843-856 DOI: 10.1002/phar.2438.

Crossref PubMed Google Scholar
32 Hashemian SMR, Sheida A, Taghizadieh M, Memar MY, Hamblin MR, Bannazadeh Baghi H, Sadri Nahand J, Asemi Z, Mirzaei H. Paxlovid (nirmatrelvir/ritonavir): a new approach to COVID-19 therapy?. Biomed Pharmacother 2023; 162: 114367 DOI: 10.1016/j.biopha.2023.114367.

Crossref PubMed Google Scholar
33 Kimata M, Watanabe A, Yanagida Y, Kinoshita D, Maekawa S. Safety and effectiveness of molnupiravir (LAGEVRIO^®) cpsules in Japanese patients with COVID-19: interim report of post-marketing surveillance in Japan. Infect Dis Ther 2023; 12: 1119-1136 DOI: 10.1007/s40121-023-00782-5.

Crossref PubMed Google Scholar
34 Yip AJW, Low ZY, Chow VTK, Lal SK. Repurposing molnupiravir for COVID-19: The mechanisms of antiviral activity. Viruses 2022; 14: 1345 DOI: 10.3390/v14061345.

Crossref PubMed Google Scholar
35 Khani E, Shahrabi M, Rezaei H, Pourkarim F, Afsharirad H, Solduzian M. Current evidence on the use of anakinra in COVID-19. Int Immunopharmacol 2022; 111: 109075 DOI: 10.1016/j.intimp.2022.109075.

Crossref PubMed Google Scholar
36 Elmekaty EZI, Maklad A, Abouelhassan R, Munir W, Ibrahim MIM, Nair A, Alibrahim R, Iqbal F, Al Bishawi A, Abdelmajid A, Aboukamar M, Hadi HA, Khattab MA, Al Soub H, Al Maslamani M. Evaluation of anakinra in the management of patients with COVID-19 infection: A randomized clinical trial. Front Microbiol 2023; 14: 1098703 DOI: 10.3389/fmicb.2023.1098703.

Crossref PubMed Google Scholar
37 Harris E. FDA approves vilobelimab for emergency use in hospitalized adults. JAMA 2023; 329: 1544 DOI: 10.1001/jama.2023.6293.

Crossref PubMed Google Scholar
38 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC. ACTT-1 Study Group Members. Remdesivir for the treatment of COVID – final report. N Engl J Med 2020; 383: 1813-1826 DOI: 10.1056/NEJMoa2007764.

Crossref PubMed Google Scholar
39 Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in Healthy Subjects. Clin Transl Sci 2020; 13: 896-906 DOI: 10.1111/cts.12840.

Crossref PubMed Google Scholar
40 Elsawah HK, Elsokary MA, Abdallah MS, ElShafie AH. Efficacy and safety of remdesivir in hospitalized Covid-19 patients: Systematic review and meta-analysis including network meta-analysis. Rev Med Virol 2021; 31: e2187 DOI: 10.1002/rmv.2187.

Crossref PubMed Google Scholar
41 Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, De Rosa R, Corcione A, Durante-Mangoni E. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int 2020; 14: 881-883 DOI: 10.1007/s12072-020-10077-3.

Crossref PubMed Google Scholar
42 Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol 2020; 18: 2835-2836 DOI: 10.1016/j.cgh.2020.07.050.

Crossref PubMed Google Scholar
43 Hu K, Guan WJ, Bi Y, Zhang W, Li L, Zhang B, Liu Q, Song Y, Li X, Duan Z, Zheng Q, Yang Z, Liang J, Han M, Ruan L, Wu C, Zhang Y, Jia ZH, Zhong NS. Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with coronavirus disease 2019: A multicenter, prospective, randomized controlled trial. Phytomedicine 2021; 85: 153242 DOI: 10.1016/j.phymed.2020.153242.

Crossref PubMed Google Scholar
44 Chantrill BH, Coulthard CE, Dickinson L, Inkley GW, Morris W, Pyle AH. The action of plant extracts on a bacteriophage of Pseudomonas pyocyanea and on influenza A virus. J Gen Microbiol 1952; 6: 74-84 DOI: 10.1099/00221287-6-1-2-74.

Crossref PubMed Google Scholar
45 Denaro M, Smeriglio A, Barreca D, De Francesco C, Occhiuto C, Milano G, Trombetta D. Antiviral activity of plants and their isolated bioactive compounds: An update. Phyther Res 2020; 34: 742-768 DOI: 10.1002/ptr.6575.

Crossref PubMed Google Scholar
46 Ali SI, Sheikh WM, Rather MA, Venkatesalu V, Muzamil Bashir S, Nabi SU. Medicinal plants: Treasure for antiviral drug discovery. Phyther Res 2021; 35: 3447-3483 DOI: 10.1002/ptr.7039.

Crossref PubMed Google Scholar
47 Ma L, Yao L. Antiviral effects of plant-derived essential oils and their components: An updated review. Molecules 2020; 25: 1-13 DOI: 10.3390/molecules25112627.

Crossref PubMed Google Scholar
48 Guerra Y, Celi D, Cueva P, Perez-Castillo Y, Giampieri F, Alvarez-Suarez JM, Tejera E. Critical review of plant-derived compounds as possible inhibitors of SARS-CoV – 2 proteases: a comparison with experimentally validated molecules. ACS Omega 2022; 7: 44542-44555 DOI: 10.1021/acsomega.2c05766.

Crossref PubMed Google Scholar
49 Yuvejwattana S. Thailand clears use of herbal medicine for COVID-19 treatment. Accessed January 3, 2023 at: https://www.bloomberg.com/news/articles/2020-12-30/thailand-clears-use-of-herbal-medicine-for-covid-19-treatment

PubMed Google Scholar
50 Wink M. Plant secondary metabolites modulate insect behavior-steps toward addiction?. Front Physiol 2018; 9: 1-9 DOI: 10.3389/fphys.2018.00364.

Crossref PubMed Google Scholar
51 Isah T. Stress and defense responses in plant secondary metabolites production. Biol Res 2019; 52: 39 DOI: 10.1186/s40659-019-0246-3.

Crossref PubMed Google Scholar
52 Jan R, Asaf S, Numan M, Lubna. Kim KM. Plant secondary metabolite biosynthesis and transcriptional regulation in response to biotic and abiotic stress conditions. Agronomy 2021; 11: 1-31 DOI: 10.3390/agronomy11050968.

Crossref PubMed Google Scholar
53 Johnson M. Wuhan 2019 novel coronavirus – 2019-nCoV. Mater Methods 2020; 10: 1-5 DOI: 10.13070/mm.en.10.2867.

Crossref PubMed Google Scholar
54 Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544 DOI: 10.1038/s41564-020-0695-z.

Crossref PubMed Google Scholar
55 Wang MY, Zhao R, Gao LJ, Gao XF, Wang DP, Cao JM. SARS-CoV-2: Structure, biology, and structure-based therapeutics development. Front Cell Infect Microbiol 2020; 10: 1-17 DOI: 10.3389/fcimb.2020.587269.

Crossref PubMed Google Scholar
56 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395: 565-574 DOI: 10.1016/S0140-6736(20)30251-8.

Crossref PubMed Google Scholar
57 Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-273 DOI: 10.1038/s41586-020-2012-7.

Crossref PubMed Google Scholar
58 Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China. Microbes Infect 2020; 22: 74-79 DOI: 10.1016/j.micinf.2020.01.003.

Crossref PubMed Google Scholar
59 Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, Sun C, Sylvia S, Rozelle S, Raat H, Zhou H. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis Poverty 2020; 9: 29 DOI: 10.1186/s40249-020-00646-x.

Crossref PubMed Google Scholar
60 van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus ADME, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RAM. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 2012; 3: e00473-12 DOI: 10.1128/mBio.00473-12.

Crossref PubMed Google Scholar
61 Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LLM, Guan Y, Rozanov M, Spaan WJM, Gorbalenya AE. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 2003; 331: 991-1004 DOI: 10.1016/s0022-2836(03)00865-9.

Crossref PubMed Google Scholar
62 Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, Haagmans BL, Lauber C, Leontovich AM, Neuman BW, Penzar D, Perlman S, Poon LLM, Samborskiy DV, Sidorov IA, Sola I, Ziebuhr J. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544 DOI: 10.1038/s41564-020-0695-z.

Crossref PubMed Google Scholar
63 Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet 2021; 397: 952-954 DOI: 10.1016/S0140-6736(21)00370-6.

Crossref PubMed Google Scholar
64 Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 2021; 398: 2126-2128 DOI: 10.1016/S0140-6736(21)02758-6.

Crossref PubMed Google Scholar
65 Sternberg A, Naujokat C. Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination. Life Sci 2020; 257: 118056 DOI: 10.1016/j.lfs.2020.118056.

Crossref PubMed Google Scholar
66 Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021; 19: 141-154 DOI: 10.1038/s41579-020-00459-7.

Crossref PubMed Google Scholar
67 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727-733 DOI: 10.1056/NEJMoa2001017.

Crossref PubMed Google Scholar
68 Yadav R, Chaudhary JK, Jain N, Chaudhary PK, Khanra S, Dhamija P, Sharma A, Kumar A, Handu S. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 2021; 10: 821 DOI: 10.3390/cells10040821.

Crossref PubMed Google Scholar
69 Chan JFW, Kok KH, Zhu Z, Chu H, To KKW, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9: 221-236 DOI: 10.1080/22221751.2020.1719902.

Crossref PubMed Google Scholar
70 Chakravarti R, Singh R, Ghosh A, Dey D, Sharma P, Velayutham R, Roy S, Ghosh D. A review on potential of natural products in the management of COVID-19. RSC Adv 2021; 11: 16711-16735 DOI: 10.1039/d1ra00644d.

Crossref PubMed Google Scholar
71 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens T, Herrler G, Wu NH, Nitsche A, Müller M, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-280 DOI: 10.1016/j.cell.2020.02.052.

Crossref PubMed Google Scholar
72 Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart R, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1-9 DOI: 10.1161/01.RES.87.5.e1.

Crossref PubMed Google Scholar
73 Chen YW, Lee MS, Lucht A, Chou FP, Huang W, Havighurst T, Kim K, Wang JK, Antalis T, Johnson M, Lin CY. TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 2010; 176: 2986-2996 DOI: 10.2353/ajpath.2010.090665.

Crossref PubMed Google Scholar
74 Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the SARS-coronavirus spike-protein. J Virol 2013; 88: 1293-1307 DOI: 10.1128/JVI.02202-13.

Crossref PubMed Google Scholar
75 Park Y. TMPRSS2 (transmembrane protease, serine 2). Atlas Genet Cytogenet Oncol Haematol 2011; 14: 1163-1165 DOI: 10.4267/2042/44922.

Crossref PubMed Google Scholar
76 Vaarala M, Porvari K, Kellokumpu S, Kyllönen A, Vihko P. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol 2001; 193: 134-140 DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T.

Crossref PubMed Google Scholar
77 Luo H, Tie L, Cao M, Hunter A, Pabst T, Du J, Field R, Li Y, Wang W. Cathepsin L causes proteolytic cleavage of CHO expressed proteins during processing and storage: identification, characterization, and mitigation. Biotechnol Prog 2018; 35: e2732 DOI: 10.1002/btpr.2732.

Crossref PubMed Google Scholar
78 Anderson E, Molloy S, Jean F, Fei H, Shimamura S. The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 2002; 277: 12879-12890 DOI: 10.1074/jbc.M108740200.

Crossref PubMed Google Scholar
79 Bisht N, Singh BK. Role of computer aided drug design in drug development and drug discovery. Int J Pharm Sci Res 2018; 9: 1405-1415 DOI: 10.13040/IJPSR.0975-8232.9(4).1405-15.

Crossref PubMed Google Scholar
80 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461 DOI: 10.1002/jcc.21334.

Crossref PubMed Google Scholar
81 Rakib A, Nain Z, Sami SA, Mahmud S, Islam A, Ahmed S, Siddiqui ABF, Babu SMOF, Hossain P, Shahriar A, Nainu F, Emran TB, Simal-Gandara J. A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: An in silico investigation. Brief Bioinform 2021; 22: 1476-1498 DOI: 10.1093/bib/bbab045.

Crossref PubMed Google Scholar
82 Rani I, Kalsi A, Kaur G, Sharma P, Gupta S, Gautam RK, Chopra H, Bibi S, Ahmad SU, Singh I, Dhawan M, Emran TB. Modern drug discovery applications for the identification of novel candidates for COVID-19 infections. Ann Med Surg 2022; 80: 104125 DOI: 10.1016/j.amsu.2022.104125.

Crossref PubMed Google Scholar
83 Yuriev E, Agostino M, Ramsland PA. Challenges and advances in computational docking: 2009 in review. J Mol Recognit 2011; 24: 149-164 DOI: 10.1002/jmr.1077.

Crossref PubMed Google Scholar
84 Ren J, He Y, Chen W, Chen T, Wang G, Wang Z, Xu Z, Luo X, Zhu W, Jiang H, Shen J, Xu Y. Thermodynamic and structural characterization of halogen bonding in protein–ligand interactions: A case study of PDE5 and its inhibitors. J Med Chem 2014; 57: 3588-3593 DOI: 10.1021/jm5002315.

Crossref PubMed Google Scholar
85 Spyrakis F, Cavasotto CN. Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description. Arch Biochem Biophys 2015; 583: 105-119 DOI: 10.1016/j.abb.2015.08.002.

Crossref PubMed Google Scholar
86 Sethi A, Joshi K, Sasikala K, Alvala M. Molecular Docking in Modern Drug Discovery: Principles and Recent Applications. In: Gaitonde V, Karmakar P, Trivedi A, eds. Drug Discovery and Development – New Advances. IntechOpen. 2020: 13

Google Scholar
87 Shoichet BK, Leach AR, Kuntz ID. Ligand solvation in molecular docking. Proteins 1999; 34: 4-16 DOI: 10.1002/(SICI)1097-0134(19990101)34:1<4::AID-PROT2>3.0.CO;2-6.

Crossref PubMed Google Scholar
88 Gupta Y, Savytskyi OV, Coban M, Venugopal A, Pleqi V, Weber CA, Chitale R, Durvasula R, Hopkins C, Kempaiah P, Caulfield TR. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med 2023; 91: 101151 DOI: 10.1016/j.mam.2022.101151.

Crossref PubMed Google Scholar
89 Freddolino PL, Harrison CB, Liu Y, Schulten K. Challenges in protein-folding simulations. Nat Phys 2010; 6: 751-758 DOI: 10.1038/nphys1713.

Crossref PubMed Google Scholar
90 Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov 2018; 13: 23-37 DOI: 10.1080/17460441.2018.1403419.

Crossref PubMed Google Scholar
91 De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of molecular dynamics and related methods in drug discovery. J Med Chem 2016; 59: 4035-4061 DOI: 10.1021/acs.jmedchem.5b01684.

Crossref PubMed Google Scholar
92 Salomon-Ferrer R, Götz AW, Poole D, Le Grand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J Chem Theory Comput 2013; 9: 3878-3888 DOI: 10.1021/ct400314y.

Crossref PubMed Google Scholar
93 Filipe HAL, Loura LMS. Molecular dynamics simulations: Advances and applications. Molecules 2022; 27: 37-47 DOI: 10.3390/molecules27072105.

Crossref PubMed Google Scholar
94 Kumar A, Choudhir G, Shukla SK, Sharma M, Tyagi P, Bhushan A, Rathore M. Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn 2021; 39: 3760-3770 DOI: 10.1080/07391102.2020.1772112.

Crossref PubMed Google Scholar
95 Muratov EN, Amaro R, Andrade CH, Brown N, Ekins S, Fourches D, Isayev O, Kozakov D, Medina-Franco JL, Merz KM, Oprea TI, Poroikov V, Schneider G, Todd MH, Varnek A, Winkler DA, Zakharov AV, Cherkasov A, Tropsha A. A critical overview of computational approaches employed for COVID-19 drug discovery. Chem Soc Rev 2021; 50: 9121-9151 DOI: 10.1039/d0cs01065k.

Crossref PubMed Google Scholar
96 Jantan I, Arshad L, Septama AW, Haque MA, Mohamed-Hussein ZA, Govender NT. Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review. Phytother Res 2023; 37: 1036-1056 DOI: 10.1002/ptr.7671.

Crossref PubMed Google Scholar
97 Lamers MM, van der Vaart J, Knoops K, Riesebosch S, Breugem TI, Mykytyn AZ, Beumer J, Schipper D, Bezstarosti K, Koopman CD, Groen N, Ravelli RBG, Duimel HQ, Demmers JAA, Verjans GMGM, Koopmans MPG, Muraro MJ, Peters PJ, Clevers H, Haagmans BL. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J 2021; 40: e105912 DOI: 10.15252/embj.2020105912.

Crossref PubMed Google Scholar
98 Bukowy-Bieryłło Z. Long-term differentiating primary human airway epithelial cell cultures: How far are we?. Cell Commun Signal 2021; 19: 63 DOI: 10.1186/s12964-021-00740-z.

Crossref PubMed Google Scholar
99 Ramirez S, Fernandez-Antunez C, Galli A, Underwood A, Pham LV, Ryberg LA, Feng S, Pedersen MS, Mikkelsen LS, Belouzard S, Dubuisson J, Sølund C, Weis N, Gottwein JM, Fahnøe U, Bukh J. Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication. Antimicrob Agents Chemother 2021; 65: e0009721 DOI: 10.1128/AAC.00097-21.

Crossref PubMed Google Scholar
100 Lamers MM, Haagmans BL. SARS-CoV-2 pathogenesis. Nat Rev Microbiol 2022; 20: 270-284 DOI: 10.1038/s41579-022-00713-0.

Crossref PubMed Google Scholar
101 Ranga A, Gjorevski N, Lutolf MP. Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev 2014; 69 – 70: 19-28 DOI: 10.1016/j.addr.2014.02.006.

Crossref PubMed Google Scholar
102 Takayama K. In vitro and animal models for SARS-CoV-2 research. Trends Pharmacol Sci 2020; 41: 513-517

Crossref PubMed Google Scholar
103 Morales-Paredes CA, Rodríguez-Díaz JM, Boluda-Botella N. Pharmaceutical compounds used in the COVID-19 pandemic: A review of their presence in water and treatment techniques for their elimination. Sci Total Environ 2022; 814: 152691 DOI: 10.1016/j.scitotenv.2021.152691.

Crossref PubMed Google Scholar
104 Khan T, Khan MA, Mashwani ZUR, Ullah N, Nadhman A. Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites. Biocatal Agric Biotechnol 2021; 31: 101890 DOI: 10.1016/j.bcab.2020.101890.

Crossref PubMed Google Scholar
105 Deng W, Xu Y, Kong Q, Xue J, Yu P, Liu J, Lv Q, Li F, Wei Q, Bao L. Therapeutic efficacy of pudilan xiaoyan oral liquid (PDL) for COVID-19 in vitro and in vivo . Signal Transduct Target Ther 2020; 5: 2-4 DOI: 10.1038/s41392-020-0176-0.

Crossref PubMed Google Scholar
106 Song J, Zhang L, Xu Y, Yang D, Yang S, Zhang W, Wang J, Tian S, Yang S, Yuan T, Liu A, Lv Q, Li F, Liu H, Hou B, Peng X, Lu Y, Du G. The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro . Biochem Pharmacol 2021; 183: 114302 DOI: 10.1016/j.bcp.2020.114302.

Crossref PubMed Google Scholar
107 Giordano D, Facchiano A, Carbone V. food plant secondary metabolites antiviral activity and their possible roles in SARS-CoV-2 treatment: An overview. Molecules 2023; 28: 2470 DOI: 10.3390/molecules28062470.

Crossref PubMed Google Scholar
108 Ahmad R, Srivastava S, Ghosh S, Khare SK. Phytochemical delivery through nanocarriers: A review. Colloids Surf B Biointerfaces 2021; 197: 111389 DOI: 10.1016/j.colsurfb.2020.111389.

Crossref PubMed Google Scholar
109 Ben-Shabat S, Yarmolinsky L, Porat D, Dahan A. Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies. Drug Deliv Transl Res 2020; 10: 354-367 DOI: 10.1007/s13346-019-00691-6.

Crossref PubMed Google Scholar
110 Hartmann T. From waste products to ecochemicals: Fifty years research of plant secondary metabolism. Phytochemistry 2007; 68: 2831-2846 DOI: 10.1016/j.phytochem.2007.09.017.

Crossref PubMed Google Scholar
111 Balandrin MF, Klocke JA, Wurtele ES, Bollinger WH. Natural plant chemicals: Sources of industrial and medicinal materials. Science 1985; 228: 1154-1160 DOI: 10.1126/science.3890182.

Crossref PubMed Google Scholar
112 Janzen DH. Secondary Plant Products. In: Bell EA, Charlwood BV, eds. Encyclopedia of Plant Physiology, New Series. Environ Conserv. Cambridge: Cambridge University Press; 1981: 79 DOI: 10.1017/S0376892900026904

Crossref Google Scholar
113 Ebenezer KS, Manivannan R, Punniyamoorthy A, Tamilselvan C. Plant secondary metabolites of antiviral properties a rich medicinal source for drug discovery: a mini review. J Drug Deliv Ther 2019; 9: 161-167 DOI: 10.22270/jddt.v9i5.3471.

Crossref PubMed Google Scholar
114 Bhuiyan FR, Howlader S, Raihan T, Hasan M. Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic. Front Med 2020; 7: 1-26 DOI: 10.3389/fmed.2020.00444.

Crossref PubMed Google Scholar
115 Hussein RA, El-Anssary AA. Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. In: Builders PF, ed. Herbal Medicine. London: Intechopen. 2018

Google Scholar
116 Carletti G, Nervo G, Cattivelli L. Flavonoids and melanins: A common strategy across two kingdoms. Int J Biol Sci 2014; 10: 1159-1170 DOI: 10.7150/ijbs.9672.

Crossref PubMed Google Scholar
117 Zakaryan H, Arabyan E, Oo A, Zandi K. Flavonoids: Promising natural compounds against viral infections. Arch Virol 2017; 162: 2539-2551 DOI: 10.1007/s00705-017-3417-y.

Crossref PubMed Google Scholar
118 Ferraz C, Teixeira de Carvalho T, Manchope M, Artero N, Rasquel-Oliveira F, Fattori V, Casagrande R, Verri W. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules 2020; DOI: 10.3390/molecules25030762.

Crossref PubMed Google Scholar
119 Anand AV, Balamuralikrishnan B, Kaviya M, Bharathi K, Parithathvi A, Arun M, Senthilkumar N, Velayuthaprabhu S, Saradhadevi M, Al-Dhabi NA, Arasu MV, Yatoo MI, Tiwari R, Dhama K. Medicinal plants, phytochemicals, and herbs to combat viral pathogens including SARS-CoV-2. Molecules 2021; 26: 1-28 DOI: 10.3390/molecules26061775.

Crossref PubMed Google Scholar
120 Ogbole O, Akinleye T, Segun P, Faleye T, Adeniji A. In vitro antiviral activity of twenty-seven medicinal plant extracts from Southwest Nigeria against three serotypes of echoviruses. Virol J 2018; 15: 110 DOI: 10.1186/s12985-018-1022-7.

Crossref PubMed Google Scholar
121 Andres A, Donovan S, Kuhlenschmidt M. Current Topics Soy isoflavones and virus infections. J Nutr Biochem 2009; 20: 563-569 DOI: 10.1016/j.jnutbio.2009.04.004.

Crossref PubMed Google Scholar
122 Ngwa W, Kumar R, Thompson D, Lyerly W, Moore R, Reid TE, Lowe H, Toyang N. Potential of flavonoid-inspired phytomedicines against COVID-19. Molecules 2020; 25: 2707 DOI: 10.3390/molecules25112707.

Crossref PubMed Google Scholar
123 Palit P, Mukhopadhyay A, Chattopadhyay D. Phyto-pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID-19, based on its promising immunomodulatory, anti-coagulant and anti-viral property. Phytother Res 2021; 35: 4246-4257 DOI: 10.1002/ptr.7084.

Crossref PubMed Google Scholar
124 Gillessen A, Schmidt HHJ. Silymarin as supportive treatment in liver diseases: A narrative review. Adv Ther 2020; 37: 1279-1301 DOI: 10.1007/s12325-020-01251-y.

Crossref PubMed Google Scholar
125 Hanafy NAN, El-Kemary MA. Silymarin/curcumin loaded albumin nanoparticles coated by chitosan as muco-inhalable delivery system observing anti-inflammatory and anti COVID-19 characterizations in oleic acid triggered lung injury and in vitro COVID-19 experiment. Int J Biol Macromol 2022; 198: 101-110 DOI: 10.1016/j.ijbiomac.2021.12.073.

Crossref PubMed Google Scholar
126 ClinicalTrials.gov. Silymarin in COVID-19 Pneumonia (SCOPE), NCT04394208. Accessed September 22, 2022 at: https://classic.clinicaltrials.gov/ct2/show/NCT04394208

PubMed Google Scholar
127 Thilakarathna SH, Rupasinghe HPV. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013; 5: 3367-3387 DOI: 10.3390/nu5093367.

Crossref PubMed Google Scholar
128 Ross JA, Kasum CM. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002; 22: 19-34 DOI: 10.1146/annurev.nutr.22.111401.144957.

Crossref PubMed Google Scholar
129 Seguin J, Brullé L, Boyer R, Lu YM, Ramos Romano M, Touil YS, Scherman D, Bessodes M, Mignet N, Chabot GG. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int J Pharm 2013; 444: 146-154 DOI: 10.1016/j.ijpharm.2013.01.050.

Crossref PubMed Google Scholar
130 Zobeiri M, Belwal T, Parvizi F, Naseri R, Farzaei MH, Nabavi SF, Sureda A, Nabavi SM. Naringenin and its nano-formulations for fatty liver: Cellular modes of action and clinical perspective. Curr Pharm Biotechnol 2018; 19: 196-205 DOI: 10.2174/1389201019666180514170122.

Crossref PubMed Google Scholar
131 David A, Arulmoli R, Parasuraman S. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn Rev 2016; 10: 84 DOI: 10.4103/0973-7847.194044.

Crossref PubMed Google Scholar
132 Chen L, Li J, Luo C, Liu H, Xu W, Chen G, Liew OW, Zhu W, Puah C, Shen X, Jiang H. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem 2007; 14: 8295-8306 DOI: 10.1016/j.bmc.2006.09.014.

Crossref PubMed Google Scholar
133 Nguyen TTH, Woo HJ, Kang HK, Nguyen V, Kim YM, Kim DW, Ahn SA, Xia Y, Kim D. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris . Biotechnol Lett 2012; 34: 831-838 DOI: 10.1007/s10529-011-0845-8.

Crossref PubMed Google Scholar
134 Zhang D, Wu K, Zhang X, Deng S, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med 2020; 18: 152-158 DOI: 10.1016/j.joim.2020.02.005.

Crossref PubMed Google Scholar
135 Sampangi-Ramaiah M, Vishwakarma R, Umashaanker R. Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 main protease. Curr Sci 2020; 118: 1087-1092 DOI: 10.18520/cs/v118/i7/1087-1092.

Crossref PubMed Google Scholar
136 Verma S, Pandey AK. Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis. 3 Biotech 2021; 11: 67 DOI: 10.1007/s13205-020-02630-6.

Crossref PubMed Google Scholar
137 Cherrak SA, Merzouk H, Mokhtari-Soulimane N. Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies. PLoS One 2020; 15: 1-14 DOI: 10.1371/journal.pone.0240653.

Crossref PubMed Google Scholar
138 Hiremath S, Kumar H, Nandan M, Muttappagol M, Shankarappa KS, Venkataravanappa V, Basha C, Reddy CNL. In silico docking analysis revealed the potential of phytochemicals present in Phyllanthus amarus and Andrographis paniculata, used in Ayurveda medicine in inhibiting SARS-CoV-2. 3 Biotech 2021; 11: 44 DOI: 10.1007/s13205-020-02578-7.

Crossref PubMed Google Scholar
139 Joshi T, Joshi T, Sharma P, Mathpal S, Pundir H, Bhatt V, Chandra S. In silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. Eur Rev Med Pharmacol Sci 2020; 24: 4529-4536 DOI: 10.26355/eurrev_202004_21036.

Crossref PubMed Google Scholar
140 Sekiou O, Bouziane I, Frissou N, Bouslama Z, Honcharova O, Djemel A, Benselhoub A. In-Silico identification of potent inhibitors of COVID-19 main protease (Mpro) from natural products. Int J Biochem Physiol 2021; 5: 000189 DOI: 10.23880/ijbp-16000189.

Crossref PubMed Google Scholar
141 Alimohammadi SZM, Hasani KM, Malekahmadi M, Persad E, Heshmati J. The effect of quercetin supplementation on clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. Food Sci Nutr 2023; DOI: 10.1002/fsn3.3715.

Crossref PubMed Google Scholar
142 Gangarapu K, Loganathan K, Devi MSS, Parameswaran S, Kanakavalli K, Kumar KM, Kumar D. In Silico computational screening of Kabasura Kudineer – official Siddha formulation and JACOM against SARS-CoV-2 spike protein. J Ayurveda Integr Med 2020; 13: 100324 DOI: 10.1016/j.jaim.2020.05.009.

Crossref PubMed Google Scholar
143 Vijayakumar B, Ramesh D, Joji A, Jayachandra Prakasan J, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020; 886: 173448 DOI: 10.1016/j.ejphar.2020.173448.

Crossref PubMed Google Scholar
144 Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity. J Agric Food Chem 2020; 68: 13982-13989 DOI: 10.1021/acs.jafc.0c05064.

Crossref PubMed Google Scholar
145 da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. Essential oils as antiviral agents. Potential of essential oils to treat SARS−COV−2 infection: An in−silico investigation. Int J Mol Sci 2020; 21: 1-37 DOI: 10.3390/ijms21103426.

Crossref PubMed Google Scholar
146 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: An in silico study for drug development. J Biomol Struct Dyn 2020; 39: 6306-6316 DOI: 10.1080/07391102.2020.1796811.

Crossref PubMed Google Scholar
147 Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 2020; 11: 1-11 DOI: 10.3389/fimmu.2020.01451.

Crossref PubMed Google Scholar
148 Mbikay M, Chrétien M. Isoquercetin as an anti-COVID-19 medication: A potential to realize. Front Pharmacol 2022; 13: 1-13 DOI: 10.3389/fphar.2022.830205.

Crossref PubMed Google Scholar
149 Fiorani M, Accorsi A, Cantoni O. Human red blood cells as a natural flavonoid reservoir. Free Radic Res 2003; 37: 1331-1338 DOI: 10.1080/10715760310001615998.

Crossref PubMed Google Scholar
150 Guo Y, Mah E, Bruno RS. Quercetin bioavailability is associated with inadequate plasma vitamin C status and greater plasma endotoxin in adults. Nutrition 2014; 30: 1279-1286 DOI: 10.1016/j.nut.2014.03.032.

Crossref PubMed Google Scholar
151 Martini S, Bonechi C, Rossi C. Interaction of quercetin and its conjugate quercetin 3-O-β-D-glucopyranoside with albumin as determined by NMR relaxation data. J Nat Prod 2008; 71: 175-178 DOI: 10.1021/np070285u.

Crossref PubMed Google Scholar
152 Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2017; 2: e89373 DOI: 10.1172/jci.insight.89373.

Crossref PubMed Google Scholar
153 Fiorani M, De Sanctis R, De Bellis R, Dachà M. Intracellular flavonoids as electron donors for extracellular ferricyanide reduction in human erythrocytes. Free Radic Biol Med 2002; 32: 64-72 DOI: 10.1016/S0891-5849(01)00762-6.

Crossref PubMed Google Scholar
154 Terao J, Murota K, Kawai Y. Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo . Food Funct 2011; 2: 11-17 DOI: 10.1039/C0FO00106F.

Crossref PubMed Google Scholar
155 Gong G, Guan YY, Zhang ZL, Rahman K, Wang SJ, Zhou S, Luan X, Zhang H. Isorhamnetin: a review of pharmacological effects. Biomed Pharmacother 2020; 128: 110301 DOI: 10.1016/j.biopha.2020.110301.

Crossref PubMed Google Scholar
156 Fan D, Zhou X, Zhao C, Chen H, Zhao Y, Gong X. Anti-inflammatory, antiviral and quantitative study of quercetin-3-O-β-D-glucuronide in Polygonum perfoliatum L. Fitoterapia 2011; 82: 805-810 DOI: 10.1016/j.fitote.2011.04.007.

Crossref PubMed Google Scholar
157 Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, Bilia A, Efferth T, Schwarz W. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med 2014; 80: 177-182 DOI: 10.1055/s-0033-1360277.

Artikel in Thieme Connect PubMed Google Scholar
158 Shaldam MA, Yahya G, Mohamed NH, Abdel-Daim MM, Al Naggar Y. In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes. Environ Sci Pollut Res Int 2021; 28: 40507-40514 DOI: 10.1007/s11356-021-14195-9.

Crossref PubMed Google Scholar
159 Saeed M, Naveed M, Arif M, Kakar M, Manzoor R, El-Hack M, Alagawany M, Tiwari R, Khandia R, Munjal A, Karthik K, Dhama K, Iqbal H, Dadar M, Sun C. Green tea (Camellia sinensis) andl-theanine: Medicinal values and beneficial applications in humans – a comprehensive review. Biomed Pharmacother 2017; 95: 1260-1275 DOI: 10.1016/j.biopha.2017.09.024.

Crossref PubMed Google Scholar
160 Jena A, Kanungo N, Nayak V, Chainy G, Dandapat J. Catechin and curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: insights from computational study and implication for intervention. 2020; 11: 2043 DOI: 10.21203/rs.3.rs-22057/v1.

Crossref PubMed Google Scholar
161 Henss L, Auste A, Schürmann C, Schmidt C, von Rhein C, Mühlebach MD, Schnierle BS. The green tea catechin epigallocatechin gallate inhibits SARS-CoV- 2 infection. J Gen Virol 2021; 102: 001574 DOI: 10.1099/jgv.0.001574.

Crossref PubMed Google Scholar
162 Mishra CB, Pandey P, Sharma RD, Malik MZ, Mongre RK, Lynn AM, Prasad R, Jeon R, Prakash A. Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: An integrated computational approach. Brief Bioinform 2021; 22: 1346-1360 DOI: 10.1093/bib/bbaa378.

Crossref PubMed Google Scholar
163 Mhatre S, Gurav N, Shah M, Patravale V. Entry-inhibitory role of catechins against SARS-CoV-2 and its UK variant. Comput Biol Med 2021; 135: 104560 DOI: 10.1016/j.compbiomed.2021.104560.

Crossref PubMed Google Scholar
164 Rabezanahary H, Badr A, Checkmahomed L, Pageau K, Desjardins Y, Baz M. Epigallocatechin gallate and isoquercetin synergize with remdesivir to reduce SARS-COV-2 replication in vitro . Front Virol 2022; 2: 1-9 DOI: 10.3389/fviro.2022.956113.

Crossref PubMed Google Scholar
165 Koch E. Previfenon® as Chemoprophylaxis of COVID-19 in Health Workers – full text view. Accessed 06.11.2023 at: https://clinicaltrials.gov/ct2/show/NCT04446065

PubMed Google Scholar
166 Song JW, Long JY, Xie L, Zhang LL, Xie QX, Chen HJ, Deng M, Li XF. Applications, phytochemistry, pharmacological effects, pharmacokinetics, toxicity of Scutellaria baicalensis Georgi. and its probably potential therapeutic effects on COVID-19: A review. Chinese Med (United Kingdom) 2020; 15: 1-26 DOI: 10.1186/s13020-020-00384-0.

Crossref PubMed Google Scholar
167 Zhao Y, Chen XY, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull 2016; 61: 1391-1398 DOI: 10.1007/s11434-016-1136-5.

Crossref PubMed Google Scholar
168 Li Y, Song K, Zhang H, Yuan M, An N, Wei Y, Wang L, Sun Y, Xing Y, Gao Y. Anti-inflammatory and immunomodulatory effects of baicalin in cerebrovascular and neurological disorders. Brain Res Bull 2020; 164: 314-324 DOI: 10.1016/j.brainresbull.2020.08.016.

Crossref PubMed Google Scholar
169 Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, Lan S, Slack RL, Kirby KA, Bassit L, Amblard F, Kim B, AbuBakar S, Sarafianos SG, Schinazi RF. Baicalein and baicalin inhibit SARS-CoV-2 RNA-Dependent-RNA polymerase. Microorganisms 2021; 9: 893 DOI: 10.3390/microorganisms9050893.

Crossref PubMed Google Scholar
170 Liu H, Ye F, Sun Q, Liang H, Li C, Li S, Lu R, Huang B, Tan W, Lai L. Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro . J Enzyme Inhib Med Chem 2021; 36: 497-503 DOI: 10.1080/14756366.2021.1873977.

Crossref PubMed Google Scholar
171 Huang S, Liu Y, Zhang Y, Zhang R, Zhu CJ, Fan L, Pei G, Zhang B, Shi Y. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduct Target Ther 2020; 5: 266 DOI: 10.1038/s41392-020-00353-x.

Crossref PubMed Google Scholar
172 Su HX, Yao S, Zhao WF, Li MJ, Liu J, Shang WJ, Xie H, Ke CQ, Hu HC, Gao MN, Yu KQ, Liu H, Shen JS, Tang W, Zhang LK, Xiao GF, Ni L, Wang DW, Zuo JP, Jiang HL, Bai F, Wu Y, Ye Y, Xu YC. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol Sin 2020; 41: 1167-1177 DOI: 10.1038/s41401-020-0483-6.

Crossref PubMed Google Scholar
173 Jo S, Kim S, Kim D, Kim MS, Shin D. Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro. J Enzyme Inhib Med Chem 2020; 35: 1539-1544 DOI: 10.1080/14756366.2020.1801672.

Crossref PubMed Google Scholar
174 Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001; 49: 3106-3112 DOI: 10.1021/jf000892m.

Crossref PubMed Google Scholar
175 Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother 2008; 62: 437-441 DOI: 10.1093/jac/dkn243.

Crossref PubMed Google Scholar
176 Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, Zhang H, Luo H, Zhu L, Jiang P, Chen L, Shen Y, Luo M, Zuo G, Hu J, Duan D, Nie Y, Shi X, Wang W, Han Y, Li T, Liu Y, Ding M, Deng H, Xu X. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004; 78: 11334-11339 DOI: 10.1128/JVI.78.20.11334-11339.2004.

Crossref PubMed Google Scholar
177 Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease 2020; 31: 179-193 DOI: 10.1007/s13337-020-00598-8.

Crossref PubMed Google Scholar
178 Xie YZ, Peng CW, Su ZQ, Huang HT, Liu XH, Zhan SF, Huang XF. A practical strategy for exploring the pharmacological mechanism of luteolin against COVID-19/asthma comorbidity: Findings of system pharmacology and bioinformatics analysis. Front Immunol 2022; 12: 1-18 DOI: 10.3389/fimmu.2021.769011.

Crossref PubMed Google Scholar
179 Di Stadio A, DʼAscanio L, Vaira LA, Cantone E, De Luca P, Cingolani C, Motta G, De Riu G, Vitelli F, Spriano G, De Vincentiis M, Camaioni A, La Mantia I, Ferreli F, Brenner MJ. Ultramicronized palmitoylethanolamide and luteolin supplement combined with olfactory training to treat post-COVID-19 olfactory impairment: A multi-center double-blinded randomized placebo- controlled clinical trial. Curr Neuropharmacol 2022; 20: 2001-2012 DOI: 10.2174/1570159x20666220420113513.

Crossref PubMed Google Scholar
180 Yu R, Chen L, Lan R, Shen R, Li P. Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking. Int J Antimicrob Agents 2020; 56: 106012 DOI: 10.1016/j.ijantimicag.2020.106012.

Crossref PubMed Google Scholar
181 Shadrack DM, Deogratias G, Kiruri LW, Onoka I, Vianney JM, Swai H, Nyandoro SS. Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics. J Mol Model 2021; 27: 221 DOI: 10.1007/s00894-021-04833-x.

Crossref PubMed Google Scholar
182 Españo E, Kim J, Lee K, Kim JK. Phytochemicals for the treatment of COVID-19. J Microbiol 2021; 59: 959-977 DOI: 10.1007/s12275-021-1467-z.

Crossref PubMed Google Scholar
183 Aniszewski T. Alkaloids – secrets of life. Amsterdam: Elsevier Science; 2007: 1-59

Google Scholar
184 Schmeller T, Latz-Brüning B, Wink M. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 1997; 44: 257-266 DOI: 10.1016/S0031-9422(96)00545-6.

Crossref PubMed Google Scholar
185 Wink M, Schimmer O. Modes of Action of Defensive Secondary Metabolites. In: Roberts JA. ed. Annual Plant Reviews Online. Hoboken: John Wiley & Sons; 2018: 21-161

Google Scholar
186 Wink M, Schmeller T, Latz-Brüning B. Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA, and other molecular targets. J Chem Ecol 1998; 24: 1881-1937.: DOI: 10.1023/A1022315802264.

Crossref PubMed Google Scholar
187 Wink M. Chapter 1 molecular modes of action of cytotoxic alkaloids: From DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance. Alkaloids Chem Biol 2007; 64: 1-47 DOI: 10.1016/S1099-4831(07)64001-2.

Crossref PubMed Google Scholar
188 Li S, Chen C, Zhang H, Guo H, Wang H, Wang L, Zhang X, Hua S, Yu J, Xiao P. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67: 18-23 DOI: 10.1016/j.antiviral.2005.02.007.

Crossref PubMed Google Scholar
189 Alfaro M, Alfaro I, Angel C. Identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthus porrigens: a molecular docking study. Chem Phys Lett 2020; 761: 138068 DOI: 10.1016/j.cplett.2020.138068.

Crossref PubMed Google Scholar
190 Borquaye L, Gasu E, Boadu G, Kyei L, Amarh M, Mensah C, Nartey D, Commodore M, Adomako A, Acheampong P, Mensah J, Mormor D. Alkaloids from Cryptolepis sanguinolenta as potential inhibitors of SARS-CoV-2 viral proteins: An in silico study. Biomed Res Int 2020; 2020: 1-14 DOI: 10.1155/2020/5324560.

Crossref PubMed Google Scholar
191 Kar P, Kumar V, Balachandar V, Sen A, Jaishee N, Anandraj A, Malhotra H, Bhattacharyya S, Mukhopadhyay S, Kinoshita M, Govindasami V, Roy A, Naidoo D, Subramaniam MD. Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: A computational investigation. J Biomol Struct Dyn 2020; 40: 4532-4542 DOI: 10.1080/07391102.2020.1860133.

Crossref PubMed Google Scholar
192 Garg S, Roy A. In silico analysis of selected alkaloids against main protease (Mpro) of SARS-CoV-2. Chem Biol Interact 2020; 332: 109309 DOI: 10.1016/j.cbi.2020.109309.

Crossref PubMed Google Scholar
193 Karatza E, Ismailos G, Karalis V. Colchicine for the treatment of COVID-19 patients: Efficacy, safety, and model informed dosage regimens. Xenobiotica 2021; 51: 643-656 DOI: 10.1080/00498254.2021.1909782.

Crossref PubMed Google Scholar
194 U. S. Food and Drug Administration. Colchicine (marketed as Colcrys) Information. Accessed March 9, 2023 at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/colchicine-marketed-colcrys-information

PubMed Google Scholar
195 Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241 DOI: 10.1038/nature04516.

Crossref PubMed Google Scholar
196 Marques-da-Silva C, Chaves MM, Castro NG, Coutinho-Silva R, Guimaraes MZP. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: Implications for its therapeutic action. Br J Pharmacol 2011; 163: 912-926 DOI: 10.1111/j.1476-5381.2011.01254.x.

Crossref PubMed Google Scholar
197 Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res 2020; 126: 1260-1280 DOI: 10.1161/CIRCRESAHA.120.315937.

Crossref PubMed Google Scholar
198 Drosos AA, Pelechas E, Drossou V, Voulgari PV. Colchicine against SARS-CoV-2 infection: What is the evidence?. Rheumatol Ther 2022; 9: 379-389 DOI: 10.1007/s40744-022-00425-0.

Crossref PubMed Google Scholar
199 Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, Metallidis S, Sianos G, Baltagiannis S, Panagopoulos P, Dolianitis K, Randou E, Syrigos K, Kotanidou A, Koulouris NG, Milionis H, Sipsas N, Gogos C, Tsoukalas G, Olympios CD, Tsagalou E, Migdalis I, Gerakari S, Angelidis C, Alexopoulos D, Davlouros P, Hahalis G, Kanonidis I, Katritsis D, Kolettis T, Manolis AS, Michalis L, Naka KK, Pyrgakis VN, Toutouzas KP, Triposkiadis F, Tsioufis K, Vavouranakis E, Martinèz-Dolz L, Reimers B, Stefanini GG, Cleman M, Goudevenos J, Tsiodras S, Tousoulis D, Iliodromitis E, Mehran R, Dangas G, Stefanadis C. GRECCO-19 investigators. Effect of colchicine vs. standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: The GRECCO-19 randomized clinical trial. JAMA Netw Open 2020; 3: e2013136 DOI: 10.1001/jamanetworkopen.2020.13136.

Crossref PubMed Google Scholar
200 Brunetti L, Diawara O, Tsai A, Firestein BL, Nahass RG, Poiani G, Schlesinger N. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med 2020; 9: 2961 DOI: 10.3390/jcm9092961.

Crossref PubMed Google Scholar
201 Della-Torre E, Della-Torre F, Kusanovic M, Scotti R, Ramirez GA, Dagna L, Tresoldi M. Treating COVID-19 with colchicine in community healthcare setting. Clin Immunol 2020; 217: 108490 DOI: 10.1016/j.clim.2020.108490.

Crossref PubMed Google Scholar
202 Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, Gigante SL, Benatti MN, Rezek UC, Emrich-Filho LL, Sousa BAA, Almeida SCL, Luppino Assad R, Veras FP, Schneider A, Rodrigues TS, Leiria LOS, Cunha LD, Alves-Filho JC, Cunha TM, Arruda E, Miranda CH, Pazin-Filho A, Auxiliadora-Martins M, Borges MC, Fonseca BAL, Bollela VR, Del-Ben CM, Cunha FQ, Zamboni DS, Santana RC, Vilar FC, Louzada-Junior P, Oliveira RDR. Beneficial effects of colchicine for moderate to severe COVID-19: A randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021; 7: e001455 DOI: 10.1136/rmdopen-2020-001455.

Crossref PubMed Google Scholar
203 Manenti L, Maggiore U, Fiaccadori E, Meschi T, Antoni AD, Nouvenne A, Ticinesi A, Cerundolo N, Prati B, Delsante M, Gandoflini I, Donghi L, Gentile M, Farina MT, Oliva V, Zambrano C, Regolisti G, Palmisano A, Caminiti C, Cocchi E, Ferrari C, Riella LV, Cravedi P, Peruzzi L. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021; 16: e0248276 DOI: 10.1371/journal.pone.0248276.

Crossref PubMed Google Scholar
204 Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol 2020; 2020: 8865954 DOI: 10.1155/2020/8865954.

Crossref PubMed Google Scholar
205 Scarsi M, Piantoni S, Colombo E, Airó P, Richini D, Miclini M, Bertasi V, Bianchi M, Bottone D, Civelli P, Cotelli MS, Damiolini E, Galbassini G, Gatta D, Ghirardelli ML, Magri R, Malamani P, Mendeni M, Molinari S, Morotti A, Salada L, Turla M, Vender A, Tincani A, Brucato A, Franceschini F, Furloni R, Andreoli L. Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome. Ann Rheum Dis 2020; 79: 1286-1289 DOI: 10.1136/annrheumdis-2020-217712.

Crossref PubMed Google Scholar
206 Tardif JC, Bouabdallaoui N, LʼAllier PL, Gaudet D, Shah B, Pillinger MH, Lopez-Sendon J, da Luz P, Verret L, Audet S, Dupuis J, Denault A, Pelletier M, Tessier PA, Samson S, Fortin D, Tardif JD, Busseuil D, Goulet E, Lacoste C, Dubois A, Joshi AY, Waters DD, Hsue P, Lepor NE, Lesage F, Sainturet N, Roy-Clavel E, Bassevitch Z, Orfanos A, Stamatescu G, Grégoire JC, Busque L, Lavallée C, Hétu PO, Paquette JS, Deftereos SG, Levesque S, Cossette M, Nozza A, Chabot-Blanchet M, Dubé MP, Guertin MC, Boivin G. COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med 2021; 9: 924-932 DOI: 10.1016/S2213-2600(21)00222-8.

Crossref PubMed Google Scholar
207 Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet Respir Med 2021; 9: 1419-1426 DOI: 10.1016/S2213-2600(21)00435-5.

Crossref PubMed Google Scholar
208 Kamran S, Sinniah A, Abdulghani MAM, Alshawsh MA. Therapeutic potential of certain terpenoids as anticancer agents: a scoping review. Cancers (Basel) 2022; 14: 1100 DOI: 10.3390/cancers14051100.

Crossref PubMed Google Scholar
209 Kulkarni S, Nagarajan SK, Ramesh V, Palaniyandi V, Sellamuthu P, Madhavan T. Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein. J Mol Struct 2020; 1221: 128823 DOI: 10.1016/j.molstruc.2020.128823.

Crossref PubMed Google Scholar
210 Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, Finamore C, Bozza S, Francisci D, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain. Front Chem 2020; 8: 1-15 DOI: 10.3389/fchem.2020.572885.

Crossref PubMed Google Scholar
211 Singh S, Florez H. Bioinformatic study to discover natural molecules with activity against COVID-19. F1000Res 2020; 9: 1203 DOI: 10.12688/f1000research.26731.1.

Crossref PubMed Google Scholar
212 Malekmohammad K, Rafieian-Kopaei M. Mechanistic aspects of medicinal plants and secondary metabolites against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Curr Pharm Des 2021; 27: 3996-4007 DOI: 10.2174/1381612827666210705160130.

Crossref PubMed Google Scholar
213 Chikhale R, Gurav S, Patil DR, Sinha DS, Prasad DS, Shakya A, Shrivastava S, Gurav N, Prasad R. Sars-CoV-2 host entry and replication inhibitors from Indian ginseng: An in-silico approach. J Biomol Struct Dyn 2020; 39: 4510-4521 DOI: 10.1080/07391102.2020.1778539.

Crossref PubMed Google Scholar
214 Siddiqui S, Upadhyay S, Ahmad R, Gupta A, Srivastava A, Trivedi A, Husain I, Ahmad B, Ahamed M, Khan MA. Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment. J Biomol Struct Dyn 2022; 40: 3928-3948 DOI: 10.1080/07391102.2020.1852117.

Crossref PubMed Google Scholar
215 Diniz LRL, Perez-Castillo Y, Elshabrawy HA, Filho CSMB, de Sousa DP. Bioactive terpenes and their derivatives as potential SARS-CoV-2 proteases inhibitors from molecular modeling studies. Biomolecules 2021; 11: 74 DOI: 10.3390/biom11010074.

Crossref PubMed Google Scholar
216 Giofrè SV, Napoli E, Iraci N, Speciale A, Cimino F, Muscarà C, Molonia MS, Ruberto G, Saija A. Interaction of selected terpenoids with two SARS-CoV-2 key therapeutic targets: An in silico study through molecular docking and dynamics simulations. Comput Biol Med 2021; 134: 104538 DOI: 10.1016/j.compbiomed.2021.104538.

Crossref PubMed Google Scholar
217 Park JY, Kim JH, Kim Y, Jeong H, Kim D, Park K, Kwon HJ, Park SC, Lee W, Ryu Y. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem 2012; 20: 5928-5935 DOI: 10.1016/j.bmc.2012.07.038.

Crossref PubMed Google Scholar
218 Falade VA, Adelusi TI, Adedotun IO, Abdul-Hammed M, Lawal TA, Agboluaje SA. In silico investigation of saponins and tannins as potential inhibitors of SARS-CoV-2 main protease (Mpro). Silico Pharmacol 2021; 9: 1-15 DOI: 10.1007/s40203-020-00071-w.

Crossref PubMed Google Scholar
219 Sun H, Xie Y, Ye YP. Advances in saponin-based adjuvants. Vaccine 2009; 27: 1787-1796 DOI: 10.1016/j.vaccine.2009.01.091.

Crossref PubMed Google Scholar
220 Skene CD, Sutton P. Saponin-adjuvanted particulate vaccines for clinical use. Methods 2006; 40: 53-59 DOI: 10.1016/j.ymeth.2006.05.019.

Crossref PubMed Google Scholar
221 Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr H. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045-2046 DOI: 10.1016/S0140-6736(03)13615-X.

Crossref PubMed Google Scholar
222 He MF, Liang JH, Shen YN, Zhang JW, Liu Y, Yang KY, Liu LC, Wang J, Xie Q, Hu C, Song X, Wang Y. Glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2. Life 2022; 12: 1706 DOI: 10.3390/life12111706.

Crossref PubMed Google Scholar
223 Behl T, Rocchetti G, Chadha S, Zengin G, Bungau S, Kumar A, Mehta V, Uddin MS, Khullar G, Setia D, Arora S, Sinan KI, Ak G, Putnik P, Gallo M, Montesano D. Phytochemicals from plant foods as potential source of antiviral agents: An overview. Pharmaceuticals 2021; 14: 1-46 DOI: 10.3390/ph14040381.

Crossref PubMed Google Scholar
224 Khalifa I, Zhu W, Mohammed HHH, Dutta K, Li C. Tannins inhibit SARS-CoV-2 through binding with catalytic dyad residues of 3CLpro: An in silico approach with 19 structural different hydrolysable tannins. J Food Biochem 2020; 44: 1-19 DOI: 10.1111/jfbc.13432.

Crossref PubMed Google Scholar
225 Wang SC, Chen Y, Wang YC, Wang WJ, Yang CS, Tsai CL, Hou MH, Chen HF, Shen YC, Hung MC. Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease. Am J Cancer Res 2020; 10: 4538-4546

PubMed Google Scholar
226 Zhang YN, Zhang QY, Li XD, Xiong J, Xiao SQ, Wang Z, Zhang ZR, Deng CL, Yang XL, Wei HP, Yuan ZM, Ye HQ, Zhang B. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect 2020; 9: 1170-1173 DOI: 10.1080/22221751.2020.1772676.

Crossref PubMed Google Scholar
227 He CL, Huang LY, Wang K, Gu CJ, Hu J, Zhang GJ, Xu W, Xie YH, Tang N, Huang AL. Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products. Signal Transduct Target Ther 2021; 6: 2020-2022 DOI: 10.1038/s41392-021-00531-5.

Crossref PubMed Google Scholar
228 Jan JT, Cheng TJR, Juang YP, Ma HH, Wu YT, Yang WB, Cheng CW, Chen X, Chou TH, Shie JJ, Cheng WC, Chein RJ, Mao SS, Liang PH, Ma C, Hung SC, Wong CH. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A 2021; 118: 1-8 DOI: 10.1073/pnas.2021579118.

Crossref PubMed Google Scholar
229 Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, Shirai T, Kanaya S, Ito Y, Kim KS, Nomura T, Suzuki T, Nishioka K, Ando S, Ejima K, Koizumi Y, Tanaka T, Aoki S, Kuramochi K, Suzuki T, Hashiguchi T, Maenaka K, Matano T, Muramatsu M, Saijo M, Aihara K, Iwami S, Takeda M, McKeating JA, Wakita T. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience 2021; 24: 102367 DOI: 10.1016/j.isci.2021.102367.

Crossref PubMed Google Scholar
230 Varghese FS, van Woudenbergh E, Overheul GJ, Eleveld MJ, Kurver L, van Heerbeek N, van Laarhoven A, Miesen P, den Hartog G, de Jonge MI, van Rij RP. Berberine and obatoclax inhibit SARS-Cov-2 replication in primary human nasal epithelial cells in vitro . Viruses 2021; 13: 282 DOI: 10.3390/v13020282.

Crossref PubMed Google Scholar
231 Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res 2020; 181: 104878 DOI: 10.1016/j.antiviral.2020.104878.

Crossref PubMed Google Scholar
232 Xia B, Shen X, He Y, Pan X, Liu FL, Wang Y, Yang F, Fang S, Wu Y, Duan Z, Zuo X, Xie Z, Jiang X, Xu L, Chi H, Li S, Meng Q, Zhou H, Zhou Y, Cheng X, Xin X, Jin L, Zhang HL, Yu DD, Li MH, Feng XL, Chen J, Jiang H, Xiao G, Zheng YT, Zhang LK, Shen J, Li J, Gao Z. SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target. Cell Res 2021; 31: 847-860 DOI: 10.1038/s41422-021-00519-4.

Crossref PubMed Google Scholar
233 Huang L, Yuen TTT, Ye Z, Liu S, Zhang G, Chu H, Yue J. Berbamine inhibits SARS-CoV-2 infection by compromising TRPMLs-mediated endolysosomal trafficking of ACE2. Signal Transduct Target Ther 2021; 6: 168 DOI: 10.1038/s41392-021-00584-6.

Crossref PubMed Google Scholar
234 Gyebi GA, Ogunro OB, Adegunloye AP, Ogunyemi OM, Afolabi SO. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): An in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn 2021; 39: 3396-3408 DOI: 10.1080/07391102.2020.1764868.

Crossref PubMed Google Scholar
235 Yang Y, Yang P, Huang C, Wu Y, Zhou Z, Wang X, Wang S. Inhibitory effect on SARS-CoV-2 infection of neferine by blocking Ca(2+) -dependent membrane fusion. J Med Virol 2021; 93: 5825-5832 DOI: 10.1002/jmv.27117.

Crossref PubMed Google Scholar
236 Choy KT, Wong AYL, Kaewpreedee P, Sia SF, Chen D, Hui KPY, Chu DKW, Chan MCW, Cheung PPH, Huang X, Peiris M, Yen HL. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro . Antiviral Res 2020; 178: 104786 DOI: 10.1016/j.antiviral.2020.104786.

Crossref PubMed Google Scholar
237 Ku KB, Shin HJ, Kim HS, Kim BT, Kim SJ, Kim C. Repurposing screens of FDA-approved drugs identify 29 inhibitors of SARS-CoV-2. J Microbiol Biotechnol 2020; 30: 1843-1853 DOI: 10.4014/JMB.2009.09009.

Crossref PubMed Google Scholar
238 Tsai YC, Lee CL, Yen HR, Chang YS, Lin YP, Huang SH, Lin CW. Antiviral action of tryptanthrin isolated from Strobilanthes cusia leaf against human coronavirus nl63. Biomolecules 2020; 10: 366 DOI: 10.3390/biom10030366.

Crossref PubMed Google Scholar
239 Fan S, Zhen Q, Chen C, Wang W, Wu Q, Ma H, Zhang C, Zhang L, Lu B, Ge H, Yong L, Li B, Yu Y, Chen W, Mao Y, Qu G, Su L, Wang A, Ding Z, Li H, Zhang J, Wang Y, Gao Y, Xu X, Zhu Z, Chen J, Zhang L, Liang H, Wu S, Huang M, Xia Q, Li P, Sun Y, Liang C, Wei W, Liu Q, Sun L. Clinical efficacy of low-dose emetine for patients with COVID-19: A real-world study. J bio-X Res 2021; 4: 53-59 DOI: 10.1097/JBR.0000000000000076.

Crossref PubMed Google Scholar
240 Kumar R, Afsar M, Khandelwal N, Chander Y, Riyesh T, Kumar R, Gulati BR, Pal Y, Barua S, Tripathi BN, Hussain T, Kumar N. Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E. Antiviral Res 2021; 189: 105056 DOI: 10.1016/j.antiviral.2021.105056.

Crossref PubMed Google Scholar
241 Wang A, Sun Y, Liu Q, Wu H, Liu J, He J, Yu J, Chen QQ, Ge Y, Zhang Z, Hu C, Chen C, Qi Z, Zou F, Liu F, Hu J, Zhao M, Huang T, Wang B, Wang L, Wang W, Wang W, Ren T, Liu J, Sun Y, Fan S, Wu Q, Liang C, Sun L, Su B, Wei W, Liu Q. Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences. Mol Biomed 2020; 1: 14 DOI: 10.1186/s43556-020-00018-9.

Crossref PubMed Google Scholar
242 Shree P, Mishra P, Selvaraj C, Singh SK, Chaube R, Garg N, Tripathi YB. Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of Ayurvedic medicinal plants – Withania somnifera (ashwagandha), Tinospora cordifolia (giloy) and Ocimum sanctum (tulsi) – a molecular docking study. J Biomol Struct Dyn 2022; 40: 190-203 DOI: 10.1080/07391102.2020.1810778.

Crossref PubMed Google Scholar
243 Mohammadi S, Heidarizadeh M, Entesari M, Esmailpour A, Esmailpour M, Moradi R, Sakhaee N, Doustkhah E. In silico investigation on the inhibiting role of nicotine/caffeine by blocking the S protein of SARS-CoV-2 versus ACE2 receptor. Microorganisms 2020; 8: 1600 DOI: 10.3390/microorganisms8101600.

Crossref PubMed Google Scholar
244 Elzupir AO. Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2. J Biomol Struct Dyn 2022; 40: 2113-2120 DOI: 10.1080/07391102.2020.1835732.

Crossref PubMed Google Scholar
245 Yang CW, Lee YZ, Hsu HY, Shih C, Chao YS, Chang HY, Lee SJ. Targeting coronaviral replication and cellular JAK2 mediated dominant NF-κB activation for comprehensive and ultimate inhibition of coronaviral activity. Sci Rep 2017; 7: 4105 DOI: 10.1038/s41598-017-04203-9.

Crossref PubMed Google Scholar
246 Yang CW, Lee YZ, Kang IJ, Barnard DL, Jan JT, Lin D, Huang CW, Yeh TK, Chao YS, Lee SJ. Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. Antiviral Res 2010; 88: 160-168 DOI: 10.1016/j.antiviral.2010.08.009.

Crossref PubMed Google Scholar
247 Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC, Chao PDL. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68: 36-42 DOI: 10.1016/j.antiviral.2005.07.002.

Crossref PubMed Google Scholar
248 Große M, Ruetalo N, Layer M, Hu D, Businger R, Rheber S, Setz C, Rauch P, Auth J, Fröba M, Brysch E, Schindler M, Schubert U. Quinine inhibits infection of human cell lines with SARS-CoV-2. Viruses 2021; 13: 647 DOI: 10.3390/v13040647.

Crossref PubMed Google Scholar
249 Clarke EC, Nofchissey RA, Ye C, Bradfute SB. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication. Glycobiology 2021; 31: 378-384 DOI: 10.1093/glycob/cwaa091.

Crossref PubMed Google Scholar
250 Raj V, Park JG, Cho KH, Choi P, Kim T, Ham J, Lee J. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. Int J Biol Macromol 2021; 168: 474-485 DOI: 10.1016/j.ijbiomac.2020.12.020.

Crossref PubMed Google Scholar
251 Nguyen LC, Yang D, Nicolaescu V, Best TJ, Gula H, Saxena D, Gabbard JD, Chen SN, Ohtsuki T, Friesen JB, Drayman N, Mohamed A, Dann C, Silva D, Robinson-Mailman L, Valdespino A, Stock L, Suárez E, Jones KA, Azizi SA, Demarco JK, Severson WE, Anderson CD, Millis JM, Dickinson BC, Tay S, Oakes SA, Pauli GF. Palmer KE; National COVID Cohort Collaborative Consortium, Meltzer DO, Randall G, Rosner MR. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv 2022; 8: eabi6110 DOI: 10.1126/sciadv.abi6110.

Crossref PubMed Google Scholar
252 van Breemen RB, Muchiri RN, Bates TA, Weinstein JB, Leier HC, Farley S, Tafesse FG. Cannabinoids block cellular entry of SARS-CoV-2 and the emerging variants. J Nat Prod 2022; 85: 176-184 DOI: 10.1021/acs.jnatprod.1c00946.

Crossref PubMed Google Scholar
253 Yang QY, Tian XY, Fang WS. Bioactive coumarins from Boenninghausenia sessilicarpa . J Asian Nat Prod Res 2007; 9: 59-65 DOI: 10.1080/10286020500382397.

Crossref PubMed Google Scholar
254 Cho JK, Curtis-Long MJ, Lee KH, Kim DW, Ryu HW, Yuk HJ, Park KH. Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa . Bioorganic Med Chem 2013; 21: 3051-3057 DOI: 10.1016/j.bmc.2013.03.027.

Crossref PubMed Google Scholar
255 Kim DW, Seo KH, Curtis-Long MJ, Oh KY, Oh JW, Cho JK, Lee KH, Park KH. Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia . J Enzyme Inhib Med Chem 2014; 29: 59-63 DOI: 10.3109/14756366.2012.753591.

Crossref PubMed Google Scholar
256 Park JY, Jeong HJ, Kim JH, Kim YM, Park SJ, Kim D, Park KH, Lee WS, Ryu YB. Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute respiratory syndrome coronavirus. Biol Pharm Bull 2012; 35: 2036-2042 DOI: 10.1248/bpb.b12-00623.

Crossref PubMed Google Scholar
257 Valizadeh H, Abdolmohammadi-Vahid S, Danshina S, Ziya Gencer M, Ammari A, Sadeghi A, Roshangar L, Aslani S, Esmaeilzadeh A, Ghaebi M, Valizadeh S, Ahmadi M. Nano-curcumin therapy, a promising method in modulating inflammatory cytokines in COVID-19 patients. Int Immunopharmacol 2020; 89: 107088 DOI: 10.1016/j.intimp.2020.107088.

Crossref PubMed Google Scholar
258 Pawar KS, Mastud RN, Pawar SK, Pawar SS, Bhoite RR, Bhoite RR, Kulkarni MV, Deshpande AR. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: A randomized clinical trial. Front Pharmacol 2021; 12: 669362 DOI: 10.3389/fphar.2021.669362.

Crossref PubMed Google Scholar
259 Goc A, Sumera W, Rath M, Niedzwiecki A. Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions. PLoS One 2021; 16: e0253489 DOI: 10.1371/journal.pone.0253489.

Crossref PubMed Google Scholar
260 Bormann M, Alt M, Schipper L, van de Sand L, Le-Trilling VTK, Rink L, Heinen N, Madel RJ, Otte M, Wuensch K, Heilingloh CS, Mueller T, Dittmer U, Elsner C, Pfaender S, Trilling M, Witzke O, Krawczyk A. Turmeric root and its bioactive ingredient curcumin effectively neutralize SARS-CoV-2 in vitro . Viruses 2021; 13: 1914 DOI: 10.3390/v13101914.

Crossref PubMed Google Scholar
261 Du R, Cooper L, Chen Z, Lee H, Rong L, Cui Q. Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro. Antiviral Res 2021; 190: 105075 DOI: 10.1016/j.antiviral.2021.105075.

Crossref PubMed Google Scholar
262 Tito A, Colantuono A, Pirone L, Pedone E, Intartaglia D, Giamundo G, Conte I, Vitaglione P, Apone F. Pomegranate peel extract as an inhibitor of SARS-CoV-2 spike binding to human ACE2 receptor (in vitro): A promising source of novel antiviral drugs. Front Chem 2021; 9: 638187 DOI: 10.3389/fchem.2021.638187.

Crossref PubMed Google Scholar
263 Nishimura H, Okamoto M, Dapat I, Katsumi M, Oshitani H. Inactivation of SARS-CoV-2 by catechins from green tea. Jpn J Infect Dis 2021; 74: 421-423 DOI: 10.7883/yoken.JJID.2020.902.

Crossref PubMed Google Scholar
264 Hong S, Seo SH, Woo SJ, Kwon Y, Song M, Ha NC. Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain. J Agric Food Chem 2021; 69: 5948-5954 DOI: 10.1021/acs.jafc.1c02050.

Crossref PubMed Google Scholar
265 Jang M, Park YI, Cha YE, Park R, Namkoong S, Lee JI, Park J. Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro . Evid Based Complement Alternat Med 2020; 2020: 1-7 DOI: 10.1155/2020/5630838.

Crossref PubMed Google Scholar
266 Ohgitani E, Shin-Ya M, Ichitani M, Kobayashi M, Takihara T, Kawamoto M, Kinugasa H, Mazda O. Significant inactivation of sars-cov-2 in vitro by a green tea catechin, a catechin-derivative, and black tea galloylated theaflavins. Molecules 2021; 26: 3572 DOI: 10.3390/molecules26123572.

Crossref PubMed Google Scholar
267 Park JY, Ko JA, Kim DW, Kim YM, Kwon HJ, Jeong HJ, Kim CY, Park KH, Lee WS, Ryu YB. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem 2016; 31: 23-30 DOI: 10.3109/14756366.2014.1003215.

Crossref PubMed Google Scholar
268 Kanjanasirirat P, Suksatu A, Manopwisedjaroen S, Munyoo B, Tuchinda P, Jearawuttanakul K, Seemakhan S, Charoensutthivarakul S, Wongtrakoongate P, Rangkasenee N, Pitiporn S, Waranuch N, Chabang N, Khemawoot P, Sa-Ngiamsuntorn K, Pewkliang Y, Thongsri P, Chutipongtanate S, Hongeng S, Borwornpinyo S, Thitithanyanont A. High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component panduratin A as anti-SARS-CoV-2 agents. Sci Rep 2020; 10: 1-12 DOI: 10.1038/s41598-020-77003-3.

Crossref PubMed Google Scholar
269 Abdallah HM, El-Halawany AM, Sirwi A, El-Araby AM, Mohamed GA, Ibrahim SRM, Koshak AE, Asfour HZ, Awan ZA, Elfaky MA. Repurposing of some natural product isolates as SARS-COV-2 main protease inhibitors via in vitro cell free and cell-based antiviral assessments and molecular modeling approaches. Pharmaceuticals (Basel) 2021; 14: 213 DOI: 10.3390/ph14030213.

Crossref PubMed Google Scholar
270 Clementi N, Scagnolari C, DʼAmore A, Palombi F, Criscuolo E, Frasca F, Pierangeli A, Mancini N, Antonelli G, Clementi M, Carpaneto A, Filippini A. Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro . Pharmacol Res 2021; 163: 12-15 DOI: 10.1016/j.phrs.2020.105255.

Crossref PubMed Google Scholar
271 Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem 2020; 35: 145-151 DOI: 10.1080/14756366.2019.1690480.

Crossref PubMed Google Scholar
272 Pitsillou E, Liang J, Ververis K, Lim KW, Hung A, Karagiannis TC. Identification of small molecule inhibitors of the deubiquitinating activity of the SARS-CoV-2 papain-like protease: in silico molecular docking studies and in vitro enzymatic activity assay. Front Chem 2020; 8: 623971 DOI: 10.3389/fchem.2020.623971.

Crossref PubMed Google Scholar
273 Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Reyburn HT, Rizzuti B, Velazquez-Campoy A. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromol 2020; 164: 1693-1703 DOI: 10.1016/j.ijbiomac.2020.07.235.

Crossref PubMed Google Scholar
274 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. J Biomol Struct Dyn 2020; 0: 1-11 DOI: 10.1080/07391102.2020.1796811.

Crossref PubMed Google Scholar
275 Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, Nguyen TTH, Park SJ, Chang JS, Park KH, Rho MC, Lee WS. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg Med Chem 2010; 18: 7940-7947 DOI: 10.1016/j.bmc.2010.09.035.

Crossref PubMed Google Scholar
276 Khan A, Wang H, Wang Y, Qiu J, Wei X, Peng S, Saleem S, Khan M, Ali S, Wei DQ. In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro). Phyther Res 2020; 35: 2841-2845 DOI: 10.1002/ptr.6998.

Crossref PubMed Google Scholar
277 Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, Keum YS, Jeong YJ. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett 2012; 22: 4049-4054 DOI: 10.1016/j.bmcl.2012.04.081.

Crossref PubMed Google Scholar
278 Su H, Yao S, Zhao W, Zhang Y, Liu J, Shao Q, Wang Q, Li M, Xie H, Shang W, Ke C, Feng L, Jiang X, Shen J, Xiao G, Jiang H, Zhang L, Ye Y, Xu Y. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun 2021; 12: 1-12 DOI: 10.1038/s41467-021-23751-3.

Crossref PubMed Google Scholar
279 Zhan Y, Ta W, Tang W, Hua R, Wang J, Wang C, Lu W. Potential antiviral activity of isorhamnetin against SARS-CoV-2 spike pseudotyped virus in vitro . Drug Dev Res 2021; 82: 1124-1130 DOI: 10.1002/ddr.21815.

Crossref PubMed Google Scholar
280 Ogunyemi OM, Gyebi GA, Elfiky AA, Afolabi SO, Ogunro OB, Adegunloye AP, Ibrahim IM. Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: an in silico perspective. Antivir Chem Chemother 2020; 28: 2040206620984076 DOI: 10.1177/2040206620984076.

Crossref PubMed Google Scholar
281 Armstrong LA, Lange SM, Cesare VD, Matthews SP, Nirujogi RS, Cole I, Hope A, Cunningham F, Toth R, Mukherjee R, Bojkova D, Gruber F, Gray D, Wyatt PG, Cinatl J, Dikic I, Davies P, Kulathu Y. Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. PLoS One 2021; 16: e0253364 DOI: 10.1371/journal.pone.0253364.

Crossref PubMed Google Scholar
282 Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007; 50: 4087-4095 DOI: 10.1021/jm070295s.

Crossref PubMed Google Scholar
283 Ma Q, Li R, Pan W, Huang W, Liu B, Xie Y, Wang Z, Li C, Jiang H, Huang J, Shi Y, Dai J, Zheng K, Li X, Hui M, Fu L, Yang Z. Phillyrin (KD-1) exerts anti-viral and anti-inflammatory activities against novel coronavirus (SARS-CoV-2) and human coronavirus 229E (HCoV-229E) by suppressing the nuclear factor kappa B (NF-κB) signaling pathway. Phytomedicine 2020; 78: 153296 DOI: 10.1016/j.phymed.2020.153296.

Crossref PubMed Google Scholar
284 Stefanik M, Strakova P, Haviernik J, Miller AD, Ruzek D, Eyer L. Antiviral activity of vacuolar ATPase blocker diphyllin against SARS-COV-2. Microorganisms 2021; 9: 1-10 DOI: 10.3390/microorganisms9030471.

Crossref PubMed Google Scholar
285 Chen Z, Cui Q, Cooper L, Zhang P, Lee H, Chen Z, Wang Y, Liu X, Rong L, Du R. Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases. Cell Biosci 2021; 11: 1-8 DOI: 10.1186/s13578-021-00564-x.

Crossref PubMed Google Scholar
286 El Gizawy HA, Boshra SA, Mostafa A, Mahmoud SH, Ismail MI, Alsfouk AA, Taher AT, Al-Karmalawy AA. Pimenta dioica (L.) merr. bioactive constituents exert anti-sars-cov-2 and anti-inflammatory activities: molecular docking and dynamics, in vitro, and in vivo studies. Molecules 2021; 26: 5844 DOI: 10.3390/molecules26195844.

Crossref PubMed Google Scholar
287 David AB, Diamant E, Dor E, Barnea A, Natan N, Levin L, Chapman S, Mimran LC, Epstein E, Zichel R, Torgeman A. Identification of SARS-CoV-2 receptor binding inhibitors by in vitro screening of drug libraries. Molecules 2021; 26: 1-12 DOI: 10.3390/molecules26113213.

Crossref PubMed Google Scholar
288 Rathinavel T, Palanisamy M, Palanisamy S, Subramanian A, Thangaswamy S. Phytochemical 6-gingerol – A promising drug of choice for COVID-19. Int J Adv Sci Eng 2020; 06: 1482-1489 DOI: 10.29294/ijase.6.4.2020.1482-1489.

Crossref PubMed Google Scholar
289 Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, Jochmans D, Leyssen P, Wang K, Neyts J, Yujie T, Blum G. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett 2021; 12: 1793-1802 DOI: 10.1021/acs.jpclett.0c03119.

Crossref PubMed Google Scholar
290 Pasquereau S, Nehme Z, Haidar Ahmad S, Daouad F, Van Assche J, Wallet C, Schwartz C, Rohr O, Morot-Bizot S, Herbein G. Resveratrol inhibits HCoV-229E and SARS-CoV-2 coronavirus replication in vitro . Viruses 2021; 13: 354 DOI: 10.3390/v13020354.

Crossref PubMed Google Scholar
291 Yang M, Wei J, Huang T, Lei L, Shen C, Lai J, Yang M, Liu L, Yang Y, Liu G, Liu Y. Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured Vero cells. Phyther Res 2021; 35: 1127-1129 DOI: 10.1002/ptr.6916.

Crossref PubMed Google Scholar
292 Ter Ellen BM, Kumar ND, Bouma EM, Troost B, van de Pol DPI, van der Ende-Metselaar HH, Apperloo L, van Gosliga D, van den Berge M, Nawijn MC, van der Voort PHJ, Moser J, Rodenhuis-Zybert IA, Smit JM. Resveratrol and pterostilbene inhibit SARS-CoV-2 replication in air–liquid interface cultured human primary bronchial epithelial cells. Viruses 2021; 13: 1335 DOI: 10.3390/v13071335.

Crossref PubMed Google Scholar
293 Pitsillou E, Liang J, Karagiannis C, Ververis K, Darmawan KK, Ng K, Hung A, Karagiannis TC. Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay. Comput Biol Chem 2020; 89: 107408 DOI: 10.1016/j.compbiolchem.2020.107408.

Crossref PubMed Google Scholar
294 Cao R, Hu H, Li Y, Wang X, Xu M, Liu J, Zhang H, Yan Y, Zhao L, Li W, Zhang T, Xiao D, Guo X, Li Y, Yang J, Hu Z, Wang M, Zhong W. Anti-SARS-CoV-2 potential of artemisinins in vitro . ACS Infect Dis 2020; 6: 2524-2531 DOI: 10.1021/acsinfecdis.0c00522.

Crossref PubMed Google Scholar
295 Nie C, Trimpert J, Moon S, Haag R, Gilmore K, Kaufer BB, Seeberger PH. In vitro efficacy of Artemisia extracts against SARS-CoV-2. Virol J 2021; 18: 1-7 DOI: 10.1186/s12985-021-01651-8.

Crossref PubMed Google Scholar
296 Nair MS, Huang Y, Fidock DA, Polyak SJ, Wagoner J, Towler MJ, Weathers PJ. Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. J Ethnopharmacol 2021; 274: 114016 DOI: 10.1016/j.jep.2021.114016.

Crossref PubMed Google Scholar
297 Zhou Y, Gilmore K, Ramirez S, Settels E, Gammeltoft KA, Pham LV, Fahnøe U, Feng S, Offersgaard A, Trimpert J, Bukh J, Osterrieder K, Gottwein JM, Seeberger PH. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci Rep 2021; 11: 14571 DOI: 10.1038/s41598-021-93361-y.

Crossref PubMed Google Scholar
298 Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, Zhang H, Yu W, Xu Q, Zou Y, Yuan Y, Guo J, Jin C, Guan X, Xie F, Song J. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomised and controlled trial. Int J Antimicrob Agents 2021; 57: 106216 DOI: 10.1016/j.ijantimicag.2020.106216.

Crossref PubMed Google Scholar
299 Sehailia M, Chemat S. Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: Potential repurposing of artenimol for COVID-19. J Biomol Struct Dyn 2021; 39: 6184-6194 DOI: 10.1080/07391102.2020.1796809.

Crossref PubMed Google Scholar
300 Lim CT, Tan KW, Wu M, Ulferts R, Armstrong LA, Ozono E, Drury LS, Milligan JC, Zeisner TU, Zeng J, Weissmann F, Canal B, Bineva-Todd G, Howell M, OʼReilly N, Beale R, Kulathu Y, Labib K, Diffley JFX. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease. Biochem J 2021; 478: 2517-2531 DOI: 10.1042/BCJ20210244.

Crossref PubMed Google Scholar
301 Zhao Y, Du X, Duan Y, Pan X, Sun Y, You T, Han L, Jin Z, Shang W, Yu J, Guo H, Liu Q, Wu Y, Peng C, Wang J, Zhu C, Yang X, Yang K, Lei Y, Guddat LW, Xu W, Xiao G, Sun L, Zhang L, Rao Z, Yang H. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell 2021; 12: 877-888 DOI: 10.1007/s13238-021-00836-9.

Crossref PubMed Google Scholar
302 Sa-Ngiamsuntorn K, Suksatu A, Pewkliang Y, Thongsri P, Kanjanasirirat P, Manopwisedjaroen S, Charoensutthivarakul S, Wongtrakoongate P, Pitiporn S, Chaopreecha J, Kongsomros S, Jearawuttanakul K, Wannalo W, Khemawoot P, Chutipongtanate S, Borwornpinyo S, Thitithanyanont A, Hongeng S. Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives. J Nat Prod 2021; 84: 1261-1270 DOI: 10.1021/acs.jnatprod.0c01324.

Crossref PubMed Google Scholar
303 Shi TH, Huang YL, Chen CC, Pi WC, Hsu YL, Lo LC, Chen WY, Fu SL, Lin CH. Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage. Biochem Biophys Res Commun 2020; 533: 467-473 DOI: 10.1016/j.bbrc.2020.08.086.

Crossref PubMed Google Scholar
304 Alhadrami HA, Sayed AM, Sharif AM, Azhar EI, Rateb ME. Olive-derived triterpenes suppress SARS-CoV-2 main protease: A promising scaffold for future therapeutics. Molecules 2021; 26: 2654 DOI: 10.3390/molecules26092654.

Crossref PubMed Google Scholar
305 Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, Park KH, Rho MC, Lee WS. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii . Bioorg Med Chem Lett 2010; 20: 1873-1876 DOI: 10.1016/j.bmcl.2010.01.152.

Crossref PubMed Google Scholar
306 van de Sand L, Bormann M, Alt M, Schipper L, Heilingloh CS, Steinmann E, Todt D, Dittmer U, Elsner C, Witzke O, Krawczyk A. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses 2021; 13: 1-10 DOI: 10.3390/v13040609.

Crossref PubMed Google Scholar
307 Srivastava V, Yadav A, Sarkar P. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc 2022; 49: 2999-3007 DOI: 10.1016/j.matpr.2020.10.055.

Crossref PubMed Google Scholar
308 Sinha SK, Shakya A, Prasad SK, Singh S, Gurav NS, Prasad RS, Gurav SS. An in-silico evaluation of different saikosaponins for their potency against SARS-CoV-2 using NSP15 and fusion spike glycoprotein as targets. J Biomol Struct Dyn 2020; 39: 1-12 DOI: 10.1080/07391102.2020.1762741.

Crossref PubMed Google Scholar
309 Kim TY, Jeon S, Jang Y, Gotina L, Won J, Ju YH, Kim S, Jang MW, Won W, Park MG, Pae AN, Han S, Kim S, Lee CJ. Platycodin D, a natural component of Platycodon grandiflorum, prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion. Exp Mol Med 2021; 53: 956-972 DOI: 10.1038/s12276-021-00624-9.

Crossref PubMed Google Scholar
310 Kumar S, Kashyap P, Chowdhury S, Kumar S, Panwar A, Kumar A. Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication. Phytomedicine 2021; 85: 153317 DOI: 10.1016/j.phymed.2020.153317.

Crossref PubMed Google Scholar
311 Cho J, Lee YJ, Kim JH, Kim SI, Kim SS, Choi BS, Choi JH. Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19. Sci Rep 2020; 10: 16200 DOI: 10.1038/s41598-020-72879-7.

Crossref PubMed Google Scholar
312 Song YH, Kim DW, Curtis-Long MJ, Yuk HJ, Wang Y, Zhuang N, Lee KH, Jeon KS, Park KH. Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits. Biol Pharm Bull 2014; 37: 1021-1028 DOI: 10.1248/bpb.b14-00026.

Crossref PubMed Google Scholar
313 Ahan RE, Hanifehnezhad A, Kehribar E, Oguzoglu TC, Földes K, Özçelik CE, Filazi N, Öztop S, Palaz F, Önder S, Bozkurt EU, Ergünay K, Özkul A, Şeker UÖŞ. A highly potent SARS-CoV-2 blocking lectin protein. ACS Infect Dis 2022; 8: 1253-1264 DOI: 10.1021/acsinfecdis.2c00006.

Crossref PubMed Google Scholar
314 Alsaidi S, Cornejal N, Mahoney O, Melo C, Verma N, Bonnaire T, Chang T, Oʼkeefe BR, Sailer J, Zydowsky TM, Teleshova N, Romero JAF. Griffithsin and carrageenan combination results in antiviral synergy against SARS-CoV-1 and 2 in a pseudoviral model. Mar Drugs 2021; 19: 1-8 DOI: 10.3390/md19080418.

Crossref PubMed Google Scholar
315 Cai Y, Xu W, Gu C, Cai X, Qu D, Lu L, Xie Y, Jiang S. Griffithsin with a broad-spectrum antiviral activity by binding glycans in viral glycoprotein exhibits strong synergistic effect in combination with a pan-coronavirus fusion inhibitor targeting SARS-CoV-2 spike S2 subunit. Virol Sin 2020; 35: 857-860 DOI: 10.1007/s12250-020-00305-3.

Crossref PubMed Google Scholar
316 OʼKeefe BR, Giomarelli B, Barnard DL, Shenoy SR, Chan PKS, McMahon JB, Palmer KE, Barnett BW, Meyerholz DK, Wohlford-Lenane CL, McCray PB. Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae . J Virol 2010; 84: 2511-2521 DOI: 10.1128/jvi.02322-09.

Crossref PubMed Google Scholar
317 Di Pierro F, Derosa G, Maffioli P, Bertuccioli A, Togni S, Riva A, Allegrini P, Khan A, Khan S, Khan BA, Altaf N, Zahid M, Ujjan ID, Nigar R, Khushk MI, Phulpoto M, Lail A, Devrajani BR, Ahmed S. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med 2021; 14: 2359-2366

Crossref PubMed Google Scholar
318 Rondanelli M, Perna S, Gasparri C, Petrangolini G, Allegrini P, Cavioni A, Faliva MA, Mansueto F, Patelli Z, Peroni G, Tartara A, Riva A. Promising effects of 3-month period of Quercetin Phytosome^® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study. Life 2022; 12: 66 DOI: 10.3390/life12010066.

Crossref PubMed Google Scholar
319 Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, Derosa G, Maffioli P, Togni S, Riva A, Allegrini P, Khan S. Potential clinical benefits of quercetin in the early stage of COVID-19: Results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med 2021; 14: 2807-2816 DOI: 10.2147/IJGM.S318949.

Crossref PubMed Google Scholar
320 McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep 2022; 12: 1-12 DOI: 10.1038/s41598-022-13920-9.

Crossref PubMed Google Scholar

Correspondence

Dr. Ali Akbar Ghotbi-Ravandi

Department of Plant Sciences and Biotechnology

Faculty of Life Sciences and Biotechnology

Shahid Beheshti University

Velenjak Street

1983963113 Tehran

Iran

Telefon: + 98 91 33 42 68 14

Fax: + 98 21 22 43 16 64

eMail: a_ghotbi@sbu.ac.ir

Publikationsverlauf

Eingereicht: 05. März 2023

Angenommen nach Revision: 10. November 2023

Accepted Manuscript online:
13. November 2023

Artikel online veröffentlicht:
07. Dezember 2023

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

References
1 COVID-19 statistics. Accessed 03.01.2023 at: https://www.worldometers.info/coronavirus

PubMed Google Scholar
2 Yang H, Bartlam M, Rao Z. Drug design targeting the main protease, the Achillesʼ heel of coronaviruses. Curr Pharm Des 2006; 12: 4573-4590 DOI: 10.2174/138161206779010369.

Crossref PubMed Google Scholar
3 Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect 2021; 54: 159-163 DOI: 10.1016/j.jmii.2020.03.022.

Crossref PubMed Google Scholar
4 Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11: 1620 DOI: 10.1038/s41467-020-15562-9.

Crossref PubMed Google Scholar
5 Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020; 176: 104742 DOI: 10.1016/j.antiviral.2020.104742.

Crossref PubMed Google Scholar
6 Liang Y, Wang ML, Chien CS, Yarmishyn AA, Yang YP, Lai WY, Luo YH, Lin YT, Chen YJ, Chang PC, Chiou SH. Highlight of immune pathogenic response and hematopathologic effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 infection. Front Immunol 2020; 11: 1022 DOI: 10.3389/fimmu.2020.01022.

Crossref PubMed Google Scholar
7 Chen B, Tian EK, He B, Tian L, Han R, Wang S, Xiang Q, Zhang S, El Arnaout T, Cheng W. Overview of lethal human coronaviruses. Signal Transduct Target Ther 2020; 5: 89 DOI: 10.1038/s41392-020-0190-2.

Crossref PubMed Google Scholar
8 Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, Wang Y, Guo X. Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020; 12: 244 DOI: 10.3390/v12020244.

Crossref PubMed Google Scholar
9 Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6: 14 DOI: 10.1038/s41421-020-0153-3.

Crossref PubMed Google Scholar
10 Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends 2020; 14: 69-71 DOI: 10.5582/bst.2020.01020.

Crossref PubMed Google Scholar
11 Cyranoski D. This scientist hopes to test coronavirus drugs on animals in locked-down Wuhan. Nature 2020; 577: 607 DOI: 10.1038/d41586-020-00190-6.

Crossref PubMed Google Scholar
12 Cohen J. New coronavirus threat galvanizes scientists. Science 2020; 367: 492-493

Crossref PubMed Google Scholar
13 Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: Progress and lessons learned. Nat Rev Drug Discov 2023; 22: 449-475 DOI: 10.1038/s41573-023-00672-y.

Crossref PubMed Google Scholar
14 Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 2021; 19: 685-700 DOI: 10.1038/s41579-021-00630-8.

Crossref PubMed Google Scholar
15 Chen Z, Du R, Galvan Achi JM, Rong L, Cui Q. SARS-CoV-2 cell entry and targeted antiviral development. Acta Pharm Sin B 2021; 11: 3879-3888 DOI: 10.1016/j.apsb.2021.05.007.

Crossref PubMed Google Scholar
16 Muralidar S, Gopal G, Visaga Ambi S. Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19. J Med Virol 2021; 93: 5260-5276 DOI: 10.1002/jmv.27019.

Crossref PubMed Google Scholar
17 Tharappel AM, Samrat SK, Li Z, Li H. Targeting crucial host factors of SARS-CoV-2. ACS Infect Dis 2020; 6: 2844-2865 DOI: 10.1021/acsinfecdis.0c00456.

Crossref PubMed Google Scholar
18 Sacco MD, Ma C, Lagarias P, Gao A, Townsend JA, Meng X, Dube P, Zhang X, Hu Y, Kitamura N, Hurst B, Tarbet B, Marty MT, Kolocouris A, Xiang Y, Chen Y, Wang J. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L. Sci Adv 2020; 6: eabe0751 DOI: 10.1126/sciadv.abe0751.

Crossref PubMed Google Scholar
19 Anirudhan V, Lee H, Cheng H, Cooper L, Rong L. Targeting SARS-CoV-2 viral proteases as a therapeutic strategy to treat COVID-19. J Med Virol 2021; 93: 2722-2734 DOI: 10.1002/jmv.26814.

Crossref PubMed Google Scholar
20 Xia Z, Sacco MD, Ma C, Townsend JA, Kitamura N, Hu Y, Ba M, Szeto T, Zhang X, Meng X, Zhang F, Xiang Y, Marty MT, Chen Y, Wang J. Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay. ACS Cent Sci 2021; 7: 1245-1260 DOI: 10.1021/acscentsci.1c00519.

Crossref PubMed Google Scholar
21 Wang Y, Anirudhan V, Du R, Cui Q, Rong L. RNA-dependent RNA polymerase of SARS-CoV-2 as a therapeutic target. J Med Virol 2021; 93: 300-310 DOI: 10.1002/jmv.26264.

Crossref PubMed Google Scholar
22 Niknam Z, Jafari A, Golchin A, Danesh Pouya F, Nemati M, Rezaei-Tavirani M, Rasmi Y. Potential therapeutic options for COVID-19: An update on current evidence. Eur J Med Res 2022; 27: 1-15 DOI: 10.1186/s40001-021-00626-3.

Crossref PubMed Google Scholar
23 Norrie JD. Remdesivir for COVID-19: challenges of underpowered studies. Lancet 2020; 395: 1525-1527 DOI: 10.1016/S0140-6736(20)31023-0.

Crossref PubMed Google Scholar
24 Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev 2023; (01) CD014962 DOI: 10.1002/14651858.CD014962.pub2.

Crossref PubMed Google Scholar
25 Tasavon Gholamhoseini M, Yazdi-Feyzabadi V, Goudarzi R, Mehrolhassani MH. Safety and efficacy of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis. J Pharm Pharm Sci 2021; 24: 237-245 DOI: 10.18433/jpps31870.

Crossref PubMed Google Scholar
26 Patel TK, Patel PB, Barvaliya M, Saurabh MK, Bhalla HL, Khosla PP. Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials. J Infect Public Health 2021; 14: 740-748 DOI: 10.1016/j.jiph.2021.03.015.

Crossref PubMed Google Scholar
27 Samaee H, Mohsenzadegan M, Ala S, Maroufi SS, Moradimajd P. Tocilizumab for treatment patients with COVID-19: recommended medication for novel disease. Int Immunopharmacol 2020; 89: 107018 DOI: 10.1016/j.intimp.2020.107018.

Crossref PubMed Google Scholar
28 Almeida PRL, Person OC, Puga MEDS, Giusti MF, Pinto ACPN, Rocha AP, Atallah ÁN. Effectiveness and safety of tocilizumab for COVID-19: A systematic review and meta-analysis of randomized clinical trials. Sao Paulo Med J 2022; 141: 168-176 DOI: 10.1590/1516-3180.2022.0170.R1.01072022.

Crossref PubMed Google Scholar
29 Sarhan NM, Warda AEA, Ibrahim HSG, Schaalan MF, Fathy SM. Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome. Sci Rep 2023; 13: 6456 DOI: 10.1038/s41598-023-33484-6.

Crossref PubMed Google Scholar
30 Richardson PJ, Robinson BWS, Smith DP, Stebbing J. The AI-assisted identification and clinical efficacy of baricitinib in the treatment of COVID-19. Vaccines 2022; 10: 951 DOI: 10.3390/vaccines10060951.

Crossref PubMed Google Scholar
31 Jorgensen SCJ, Tse CLY, Burry L, Dresser LD. Baricitinib: A review of pharmacology, safety, and emerging clinical experience in COVID-19. Pharmacotherapy 2020; 40: 843-856 DOI: 10.1002/phar.2438.

Crossref PubMed Google Scholar
32 Hashemian SMR, Sheida A, Taghizadieh M, Memar MY, Hamblin MR, Bannazadeh Baghi H, Sadri Nahand J, Asemi Z, Mirzaei H. Paxlovid (nirmatrelvir/ritonavir): a new approach to COVID-19 therapy?. Biomed Pharmacother 2023; 162: 114367 DOI: 10.1016/j.biopha.2023.114367.

Crossref PubMed Google Scholar
33 Kimata M, Watanabe A, Yanagida Y, Kinoshita D, Maekawa S. Safety and effectiveness of molnupiravir (LAGEVRIO^®) cpsules in Japanese patients with COVID-19: interim report of post-marketing surveillance in Japan. Infect Dis Ther 2023; 12: 1119-1136 DOI: 10.1007/s40121-023-00782-5.

Crossref PubMed Google Scholar
34 Yip AJW, Low ZY, Chow VTK, Lal SK. Repurposing molnupiravir for COVID-19: The mechanisms of antiviral activity. Viruses 2022; 14: 1345 DOI: 10.3390/v14061345.

Crossref PubMed Google Scholar
35 Khani E, Shahrabi M, Rezaei H, Pourkarim F, Afsharirad H, Solduzian M. Current evidence on the use of anakinra in COVID-19. Int Immunopharmacol 2022; 111: 109075 DOI: 10.1016/j.intimp.2022.109075.

Crossref PubMed Google Scholar
36 Elmekaty EZI, Maklad A, Abouelhassan R, Munir W, Ibrahim MIM, Nair A, Alibrahim R, Iqbal F, Al Bishawi A, Abdelmajid A, Aboukamar M, Hadi HA, Khattab MA, Al Soub H, Al Maslamani M. Evaluation of anakinra in the management of patients with COVID-19 infection: A randomized clinical trial. Front Microbiol 2023; 14: 1098703 DOI: 10.3389/fmicb.2023.1098703.

Crossref PubMed Google Scholar
37 Harris E. FDA approves vilobelimab for emergency use in hospitalized adults. JAMA 2023; 329: 1544 DOI: 10.1001/jama.2023.6293.

Crossref PubMed Google Scholar
38 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC. ACTT-1 Study Group Members. Remdesivir for the treatment of COVID – final report. N Engl J Med 2020; 383: 1813-1826 DOI: 10.1056/NEJMoa2007764.

Crossref PubMed Google Scholar
39 Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in Healthy Subjects. Clin Transl Sci 2020; 13: 896-906 DOI: 10.1111/cts.12840.

Crossref PubMed Google Scholar
40 Elsawah HK, Elsokary MA, Abdallah MS, ElShafie AH. Efficacy and safety of remdesivir in hospitalized Covid-19 patients: Systematic review and meta-analysis including network meta-analysis. Rev Med Virol 2021; 31: e2187 DOI: 10.1002/rmv.2187.

Crossref PubMed Google Scholar
41 Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, De Rosa R, Corcione A, Durante-Mangoni E. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int 2020; 14: 881-883 DOI: 10.1007/s12072-020-10077-3.

Crossref PubMed Google Scholar
42 Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol 2020; 18: 2835-2836 DOI: 10.1016/j.cgh.2020.07.050.

Crossref PubMed Google Scholar
43 Hu K, Guan WJ, Bi Y, Zhang W, Li L, Zhang B, Liu Q, Song Y, Li X, Duan Z, Zheng Q, Yang Z, Liang J, Han M, Ruan L, Wu C, Zhang Y, Jia ZH, Zhong NS. Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with coronavirus disease 2019: A multicenter, prospective, randomized controlled trial. Phytomedicine 2021; 85: 153242 DOI: 10.1016/j.phymed.2020.153242.

Crossref PubMed Google Scholar
44 Chantrill BH, Coulthard CE, Dickinson L, Inkley GW, Morris W, Pyle AH. The action of plant extracts on a bacteriophage of Pseudomonas pyocyanea and on influenza A virus. J Gen Microbiol 1952; 6: 74-84 DOI: 10.1099/00221287-6-1-2-74.

Crossref PubMed Google Scholar
45 Denaro M, Smeriglio A, Barreca D, De Francesco C, Occhiuto C, Milano G, Trombetta D. Antiviral activity of plants and their isolated bioactive compounds: An update. Phyther Res 2020; 34: 742-768 DOI: 10.1002/ptr.6575.

Crossref PubMed Google Scholar
46 Ali SI, Sheikh WM, Rather MA, Venkatesalu V, Muzamil Bashir S, Nabi SU. Medicinal plants: Treasure for antiviral drug discovery. Phyther Res 2021; 35: 3447-3483 DOI: 10.1002/ptr.7039.

Crossref PubMed Google Scholar
47 Ma L, Yao L. Antiviral effects of plant-derived essential oils and their components: An updated review. Molecules 2020; 25: 1-13 DOI: 10.3390/molecules25112627.

Crossref PubMed Google Scholar
48 Guerra Y, Celi D, Cueva P, Perez-Castillo Y, Giampieri F, Alvarez-Suarez JM, Tejera E. Critical review of plant-derived compounds as possible inhibitors of SARS-CoV – 2 proteases: a comparison with experimentally validated molecules. ACS Omega 2022; 7: 44542-44555 DOI: 10.1021/acsomega.2c05766.

Crossref PubMed Google Scholar
49 Yuvejwattana S. Thailand clears use of herbal medicine for COVID-19 treatment. Accessed January 3, 2023 at: https://www.bloomberg.com/news/articles/2020-12-30/thailand-clears-use-of-herbal-medicine-for-covid-19-treatment

PubMed Google Scholar
50 Wink M. Plant secondary metabolites modulate insect behavior-steps toward addiction?. Front Physiol 2018; 9: 1-9 DOI: 10.3389/fphys.2018.00364.

Crossref PubMed Google Scholar
51 Isah T. Stress and defense responses in plant secondary metabolites production. Biol Res 2019; 52: 39 DOI: 10.1186/s40659-019-0246-3.

Crossref PubMed Google Scholar
52 Jan R, Asaf S, Numan M, Lubna. Kim KM. Plant secondary metabolite biosynthesis and transcriptional regulation in response to biotic and abiotic stress conditions. Agronomy 2021; 11: 1-31 DOI: 10.3390/agronomy11050968.

Crossref PubMed Google Scholar
53 Johnson M. Wuhan 2019 novel coronavirus – 2019-nCoV. Mater Methods 2020; 10: 1-5 DOI: 10.13070/mm.en.10.2867.

Crossref PubMed Google Scholar
54 Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544 DOI: 10.1038/s41564-020-0695-z.

Crossref PubMed Google Scholar
55 Wang MY, Zhao R, Gao LJ, Gao XF, Wang DP, Cao JM. SARS-CoV-2: Structure, biology, and structure-based therapeutics development. Front Cell Infect Microbiol 2020; 10: 1-17 DOI: 10.3389/fcimb.2020.587269.

Crossref PubMed Google Scholar
56 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395: 565-574 DOI: 10.1016/S0140-6736(20)30251-8.

Crossref PubMed Google Scholar
57 Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-273 DOI: 10.1038/s41586-020-2012-7.

Crossref PubMed Google Scholar
58 Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China. Microbes Infect 2020; 22: 74-79 DOI: 10.1016/j.micinf.2020.01.003.

Crossref PubMed Google Scholar
59 Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, Sun C, Sylvia S, Rozelle S, Raat H, Zhou H. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis Poverty 2020; 9: 29 DOI: 10.1186/s40249-020-00646-x.

Crossref PubMed Google Scholar
60 van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus ADME, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RAM. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 2012; 3: e00473-12 DOI: 10.1128/mBio.00473-12.

Crossref PubMed Google Scholar
61 Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LLM, Guan Y, Rozanov M, Spaan WJM, Gorbalenya AE. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 2003; 331: 991-1004 DOI: 10.1016/s0022-2836(03)00865-9.

Crossref PubMed Google Scholar
62 Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, Haagmans BL, Lauber C, Leontovich AM, Neuman BW, Penzar D, Perlman S, Poon LLM, Samborskiy DV, Sidorov IA, Sola I, Ziebuhr J. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544 DOI: 10.1038/s41564-020-0695-z.

Crossref PubMed Google Scholar
63 Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet 2021; 397: 952-954 DOI: 10.1016/S0140-6736(21)00370-6.

Crossref PubMed Google Scholar
64 Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 2021; 398: 2126-2128 DOI: 10.1016/S0140-6736(21)02758-6.

Crossref PubMed Google Scholar
65 Sternberg A, Naujokat C. Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination. Life Sci 2020; 257: 118056 DOI: 10.1016/j.lfs.2020.118056.

Crossref PubMed Google Scholar
66 Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021; 19: 141-154 DOI: 10.1038/s41579-020-00459-7.

Crossref PubMed Google Scholar
67 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727-733 DOI: 10.1056/NEJMoa2001017.

Crossref PubMed Google Scholar
68 Yadav R, Chaudhary JK, Jain N, Chaudhary PK, Khanra S, Dhamija P, Sharma A, Kumar A, Handu S. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 2021; 10: 821 DOI: 10.3390/cells10040821.

Crossref PubMed Google Scholar
69 Chan JFW, Kok KH, Zhu Z, Chu H, To KKW, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9: 221-236 DOI: 10.1080/22221751.2020.1719902.

Crossref PubMed Google Scholar
70 Chakravarti R, Singh R, Ghosh A, Dey D, Sharma P, Velayutham R, Roy S, Ghosh D. A review on potential of natural products in the management of COVID-19. RSC Adv 2021; 11: 16711-16735 DOI: 10.1039/d1ra00644d.

Crossref PubMed Google Scholar
71 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens T, Herrler G, Wu NH, Nitsche A, Müller M, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-280 DOI: 10.1016/j.cell.2020.02.052.

Crossref PubMed Google Scholar
72 Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart R, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1-9 DOI: 10.1161/01.RES.87.5.e1.

Crossref PubMed Google Scholar
73 Chen YW, Lee MS, Lucht A, Chou FP, Huang W, Havighurst T, Kim K, Wang JK, Antalis T, Johnson M, Lin CY. TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 2010; 176: 2986-2996 DOI: 10.2353/ajpath.2010.090665.

Crossref PubMed Google Scholar
74 Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the SARS-coronavirus spike-protein. J Virol 2013; 88: 1293-1307 DOI: 10.1128/JVI.02202-13.

Crossref PubMed Google Scholar
75 Park Y. TMPRSS2 (transmembrane protease, serine 2). Atlas Genet Cytogenet Oncol Haematol 2011; 14: 1163-1165 DOI: 10.4267/2042/44922.

Crossref PubMed Google Scholar
76 Vaarala M, Porvari K, Kellokumpu S, Kyllönen A, Vihko P. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol 2001; 193: 134-140 DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T.

Crossref PubMed Google Scholar
77 Luo H, Tie L, Cao M, Hunter A, Pabst T, Du J, Field R, Li Y, Wang W. Cathepsin L causes proteolytic cleavage of CHO expressed proteins during processing and storage: identification, characterization, and mitigation. Biotechnol Prog 2018; 35: e2732 DOI: 10.1002/btpr.2732.

Crossref PubMed Google Scholar
78 Anderson E, Molloy S, Jean F, Fei H, Shimamura S. The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 2002; 277: 12879-12890 DOI: 10.1074/jbc.M108740200.

Crossref PubMed Google Scholar
79 Bisht N, Singh BK. Role of computer aided drug design in drug development and drug discovery. Int J Pharm Sci Res 2018; 9: 1405-1415 DOI: 10.13040/IJPSR.0975-8232.9(4).1405-15.

Crossref PubMed Google Scholar
80 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461 DOI: 10.1002/jcc.21334.

Crossref PubMed Google Scholar
81 Rakib A, Nain Z, Sami SA, Mahmud S, Islam A, Ahmed S, Siddiqui ABF, Babu SMOF, Hossain P, Shahriar A, Nainu F, Emran TB, Simal-Gandara J. A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: An in silico investigation. Brief Bioinform 2021; 22: 1476-1498 DOI: 10.1093/bib/bbab045.

Crossref PubMed Google Scholar
82 Rani I, Kalsi A, Kaur G, Sharma P, Gupta S, Gautam RK, Chopra H, Bibi S, Ahmad SU, Singh I, Dhawan M, Emran TB. Modern drug discovery applications for the identification of novel candidates for COVID-19 infections. Ann Med Surg 2022; 80: 104125 DOI: 10.1016/j.amsu.2022.104125.

Crossref PubMed Google Scholar
83 Yuriev E, Agostino M, Ramsland PA. Challenges and advances in computational docking: 2009 in review. J Mol Recognit 2011; 24: 149-164 DOI: 10.1002/jmr.1077.

Crossref PubMed Google Scholar
84 Ren J, He Y, Chen W, Chen T, Wang G, Wang Z, Xu Z, Luo X, Zhu W, Jiang H, Shen J, Xu Y. Thermodynamic and structural characterization of halogen bonding in protein–ligand interactions: A case study of PDE5 and its inhibitors. J Med Chem 2014; 57: 3588-3593 DOI: 10.1021/jm5002315.

Crossref PubMed Google Scholar
85 Spyrakis F, Cavasotto CN. Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description. Arch Biochem Biophys 2015; 583: 105-119 DOI: 10.1016/j.abb.2015.08.002.

Crossref PubMed Google Scholar
86 Sethi A, Joshi K, Sasikala K, Alvala M. Molecular Docking in Modern Drug Discovery: Principles and Recent Applications. In: Gaitonde V, Karmakar P, Trivedi A, eds. Drug Discovery and Development – New Advances. IntechOpen. 2020: 13

Google Scholar
87 Shoichet BK, Leach AR, Kuntz ID. Ligand solvation in molecular docking. Proteins 1999; 34: 4-16 DOI: 10.1002/(SICI)1097-0134(19990101)34:1<4::AID-PROT2>3.0.CO;2-6.

Crossref PubMed Google Scholar
88 Gupta Y, Savytskyi OV, Coban M, Venugopal A, Pleqi V, Weber CA, Chitale R, Durvasula R, Hopkins C, Kempaiah P, Caulfield TR. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med 2023; 91: 101151 DOI: 10.1016/j.mam.2022.101151.

Crossref PubMed Google Scholar
89 Freddolino PL, Harrison CB, Liu Y, Schulten K. Challenges in protein-folding simulations. Nat Phys 2010; 6: 751-758 DOI: 10.1038/nphys1713.

Crossref PubMed Google Scholar
90 Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov 2018; 13: 23-37 DOI: 10.1080/17460441.2018.1403419.

Crossref PubMed Google Scholar
91 De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of molecular dynamics and related methods in drug discovery. J Med Chem 2016; 59: 4035-4061 DOI: 10.1021/acs.jmedchem.5b01684.

Crossref PubMed Google Scholar
92 Salomon-Ferrer R, Götz AW, Poole D, Le Grand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J Chem Theory Comput 2013; 9: 3878-3888 DOI: 10.1021/ct400314y.

Crossref PubMed Google Scholar
93 Filipe HAL, Loura LMS. Molecular dynamics simulations: Advances and applications. Molecules 2022; 27: 37-47 DOI: 10.3390/molecules27072105.

Crossref PubMed Google Scholar
94 Kumar A, Choudhir G, Shukla SK, Sharma M, Tyagi P, Bhushan A, Rathore M. Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn 2021; 39: 3760-3770 DOI: 10.1080/07391102.2020.1772112.

Crossref PubMed Google Scholar
95 Muratov EN, Amaro R, Andrade CH, Brown N, Ekins S, Fourches D, Isayev O, Kozakov D, Medina-Franco JL, Merz KM, Oprea TI, Poroikov V, Schneider G, Todd MH, Varnek A, Winkler DA, Zakharov AV, Cherkasov A, Tropsha A. A critical overview of computational approaches employed for COVID-19 drug discovery. Chem Soc Rev 2021; 50: 9121-9151 DOI: 10.1039/d0cs01065k.

Crossref PubMed Google Scholar
96 Jantan I, Arshad L, Septama AW, Haque MA, Mohamed-Hussein ZA, Govender NT. Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review. Phytother Res 2023; 37: 1036-1056 DOI: 10.1002/ptr.7671.

Crossref PubMed Google Scholar
97 Lamers MM, van der Vaart J, Knoops K, Riesebosch S, Breugem TI, Mykytyn AZ, Beumer J, Schipper D, Bezstarosti K, Koopman CD, Groen N, Ravelli RBG, Duimel HQ, Demmers JAA, Verjans GMGM, Koopmans MPG, Muraro MJ, Peters PJ, Clevers H, Haagmans BL. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J 2021; 40: e105912 DOI: 10.15252/embj.2020105912.

Crossref PubMed Google Scholar
98 Bukowy-Bieryłło Z. Long-term differentiating primary human airway epithelial cell cultures: How far are we?. Cell Commun Signal 2021; 19: 63 DOI: 10.1186/s12964-021-00740-z.

Crossref PubMed Google Scholar
99 Ramirez S, Fernandez-Antunez C, Galli A, Underwood A, Pham LV, Ryberg LA, Feng S, Pedersen MS, Mikkelsen LS, Belouzard S, Dubuisson J, Sølund C, Weis N, Gottwein JM, Fahnøe U, Bukh J. Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication. Antimicrob Agents Chemother 2021; 65: e0009721 DOI: 10.1128/AAC.00097-21.

Crossref PubMed Google Scholar
100 Lamers MM, Haagmans BL. SARS-CoV-2 pathogenesis. Nat Rev Microbiol 2022; 20: 270-284 DOI: 10.1038/s41579-022-00713-0.

Crossref PubMed Google Scholar
101 Ranga A, Gjorevski N, Lutolf MP. Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev 2014; 69 – 70: 19-28 DOI: 10.1016/j.addr.2014.02.006.

Crossref PubMed Google Scholar
102 Takayama K. In vitro and animal models for SARS-CoV-2 research. Trends Pharmacol Sci 2020; 41: 513-517

Crossref PubMed Google Scholar
103 Morales-Paredes CA, Rodríguez-Díaz JM, Boluda-Botella N. Pharmaceutical compounds used in the COVID-19 pandemic: A review of their presence in water and treatment techniques for their elimination. Sci Total Environ 2022; 814: 152691 DOI: 10.1016/j.scitotenv.2021.152691.

Crossref PubMed Google Scholar
104 Khan T, Khan MA, Mashwani ZUR, Ullah N, Nadhman A. Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites. Biocatal Agric Biotechnol 2021; 31: 101890 DOI: 10.1016/j.bcab.2020.101890.

Crossref PubMed Google Scholar
105 Deng W, Xu Y, Kong Q, Xue J, Yu P, Liu J, Lv Q, Li F, Wei Q, Bao L. Therapeutic efficacy of pudilan xiaoyan oral liquid (PDL) for COVID-19 in vitro and in vivo . Signal Transduct Target Ther 2020; 5: 2-4 DOI: 10.1038/s41392-020-0176-0.

Crossref PubMed Google Scholar
106 Song J, Zhang L, Xu Y, Yang D, Yang S, Zhang W, Wang J, Tian S, Yang S, Yuan T, Liu A, Lv Q, Li F, Liu H, Hou B, Peng X, Lu Y, Du G. The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro . Biochem Pharmacol 2021; 183: 114302 DOI: 10.1016/j.bcp.2020.114302.

Crossref PubMed Google Scholar
107 Giordano D, Facchiano A, Carbone V. food plant secondary metabolites antiviral activity and their possible roles in SARS-CoV-2 treatment: An overview. Molecules 2023; 28: 2470 DOI: 10.3390/molecules28062470.

Crossref PubMed Google Scholar
108 Ahmad R, Srivastava S, Ghosh S, Khare SK. Phytochemical delivery through nanocarriers: A review. Colloids Surf B Biointerfaces 2021; 197: 111389 DOI: 10.1016/j.colsurfb.2020.111389.

Crossref PubMed Google Scholar
109 Ben-Shabat S, Yarmolinsky L, Porat D, Dahan A. Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies. Drug Deliv Transl Res 2020; 10: 354-367 DOI: 10.1007/s13346-019-00691-6.

Crossref PubMed Google Scholar
110 Hartmann T. From waste products to ecochemicals: Fifty years research of plant secondary metabolism. Phytochemistry 2007; 68: 2831-2846 DOI: 10.1016/j.phytochem.2007.09.017.

Crossref PubMed Google Scholar
111 Balandrin MF, Klocke JA, Wurtele ES, Bollinger WH. Natural plant chemicals: Sources of industrial and medicinal materials. Science 1985; 228: 1154-1160 DOI: 10.1126/science.3890182.

Crossref PubMed Google Scholar
112 Janzen DH. Secondary Plant Products. In: Bell EA, Charlwood BV, eds. Encyclopedia of Plant Physiology, New Series. Environ Conserv. Cambridge: Cambridge University Press; 1981: 79 DOI: 10.1017/S0376892900026904

Crossref Google Scholar
113 Ebenezer KS, Manivannan R, Punniyamoorthy A, Tamilselvan C. Plant secondary metabolites of antiviral properties a rich medicinal source for drug discovery: a mini review. J Drug Deliv Ther 2019; 9: 161-167 DOI: 10.22270/jddt.v9i5.3471.

Crossref PubMed Google Scholar
114 Bhuiyan FR, Howlader S, Raihan T, Hasan M. Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic. Front Med 2020; 7: 1-26 DOI: 10.3389/fmed.2020.00444.

Crossref PubMed Google Scholar
115 Hussein RA, El-Anssary AA. Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. In: Builders PF, ed. Herbal Medicine. London: Intechopen. 2018

Google Scholar
116 Carletti G, Nervo G, Cattivelli L. Flavonoids and melanins: A common strategy across two kingdoms. Int J Biol Sci 2014; 10: 1159-1170 DOI: 10.7150/ijbs.9672.

Crossref PubMed Google Scholar
117 Zakaryan H, Arabyan E, Oo A, Zandi K. Flavonoids: Promising natural compounds against viral infections. Arch Virol 2017; 162: 2539-2551 DOI: 10.1007/s00705-017-3417-y.

Crossref PubMed Google Scholar
118 Ferraz C, Teixeira de Carvalho T, Manchope M, Artero N, Rasquel-Oliveira F, Fattori V, Casagrande R, Verri W. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules 2020; DOI: 10.3390/molecules25030762.

Crossref PubMed Google Scholar
119 Anand AV, Balamuralikrishnan B, Kaviya M, Bharathi K, Parithathvi A, Arun M, Senthilkumar N, Velayuthaprabhu S, Saradhadevi M, Al-Dhabi NA, Arasu MV, Yatoo MI, Tiwari R, Dhama K. Medicinal plants, phytochemicals, and herbs to combat viral pathogens including SARS-CoV-2. Molecules 2021; 26: 1-28 DOI: 10.3390/molecules26061775.

Crossref PubMed Google Scholar
120 Ogbole O, Akinleye T, Segun P, Faleye T, Adeniji A. In vitro antiviral activity of twenty-seven medicinal plant extracts from Southwest Nigeria against three serotypes of echoviruses. Virol J 2018; 15: 110 DOI: 10.1186/s12985-018-1022-7.

Crossref PubMed Google Scholar
121 Andres A, Donovan S, Kuhlenschmidt M. Current Topics Soy isoflavones and virus infections. J Nutr Biochem 2009; 20: 563-569 DOI: 10.1016/j.jnutbio.2009.04.004.

Crossref PubMed Google Scholar
122 Ngwa W, Kumar R, Thompson D, Lyerly W, Moore R, Reid TE, Lowe H, Toyang N. Potential of flavonoid-inspired phytomedicines against COVID-19. Molecules 2020; 25: 2707 DOI: 10.3390/molecules25112707.

Crossref PubMed Google Scholar
123 Palit P, Mukhopadhyay A, Chattopadhyay D. Phyto-pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID-19, based on its promising immunomodulatory, anti-coagulant and anti-viral property. Phytother Res 2021; 35: 4246-4257 DOI: 10.1002/ptr.7084.

Crossref PubMed Google Scholar
124 Gillessen A, Schmidt HHJ. Silymarin as supportive treatment in liver diseases: A narrative review. Adv Ther 2020; 37: 1279-1301 DOI: 10.1007/s12325-020-01251-y.

Crossref PubMed Google Scholar
125 Hanafy NAN, El-Kemary MA. Silymarin/curcumin loaded albumin nanoparticles coated by chitosan as muco-inhalable delivery system observing anti-inflammatory and anti COVID-19 characterizations in oleic acid triggered lung injury and in vitro COVID-19 experiment. Int J Biol Macromol 2022; 198: 101-110 DOI: 10.1016/j.ijbiomac.2021.12.073.

Crossref PubMed Google Scholar
126 ClinicalTrials.gov. Silymarin in COVID-19 Pneumonia (SCOPE), NCT04394208. Accessed September 22, 2022 at: https://classic.clinicaltrials.gov/ct2/show/NCT04394208

PubMed Google Scholar
127 Thilakarathna SH, Rupasinghe HPV. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013; 5: 3367-3387 DOI: 10.3390/nu5093367.

Crossref PubMed Google Scholar
128 Ross JA, Kasum CM. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002; 22: 19-34 DOI: 10.1146/annurev.nutr.22.111401.144957.

Crossref PubMed Google Scholar
129 Seguin J, Brullé L, Boyer R, Lu YM, Ramos Romano M, Touil YS, Scherman D, Bessodes M, Mignet N, Chabot GG. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int J Pharm 2013; 444: 146-154 DOI: 10.1016/j.ijpharm.2013.01.050.

Crossref PubMed Google Scholar
130 Zobeiri M, Belwal T, Parvizi F, Naseri R, Farzaei MH, Nabavi SF, Sureda A, Nabavi SM. Naringenin and its nano-formulations for fatty liver: Cellular modes of action and clinical perspective. Curr Pharm Biotechnol 2018; 19: 196-205 DOI: 10.2174/1389201019666180514170122.

Crossref PubMed Google Scholar
131 David A, Arulmoli R, Parasuraman S. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn Rev 2016; 10: 84 DOI: 10.4103/0973-7847.194044.

Crossref PubMed Google Scholar
132 Chen L, Li J, Luo C, Liu H, Xu W, Chen G, Liew OW, Zhu W, Puah C, Shen X, Jiang H. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem 2007; 14: 8295-8306 DOI: 10.1016/j.bmc.2006.09.014.

Crossref PubMed Google Scholar
133 Nguyen TTH, Woo HJ, Kang HK, Nguyen V, Kim YM, Kim DW, Ahn SA, Xia Y, Kim D. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris . Biotechnol Lett 2012; 34: 831-838 DOI: 10.1007/s10529-011-0845-8.

Crossref PubMed Google Scholar
134 Zhang D, Wu K, Zhang X, Deng S, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med 2020; 18: 152-158 DOI: 10.1016/j.joim.2020.02.005.

Crossref PubMed Google Scholar
135 Sampangi-Ramaiah M, Vishwakarma R, Umashaanker R. Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 main protease. Curr Sci 2020; 118: 1087-1092 DOI: 10.18520/cs/v118/i7/1087-1092.

Crossref PubMed Google Scholar
136 Verma S, Pandey AK. Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis. 3 Biotech 2021; 11: 67 DOI: 10.1007/s13205-020-02630-6.

Crossref PubMed Google Scholar
137 Cherrak SA, Merzouk H, Mokhtari-Soulimane N. Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies. PLoS One 2020; 15: 1-14 DOI: 10.1371/journal.pone.0240653.

Crossref PubMed Google Scholar
138 Hiremath S, Kumar H, Nandan M, Muttappagol M, Shankarappa KS, Venkataravanappa V, Basha C, Reddy CNL. In silico docking analysis revealed the potential of phytochemicals present in Phyllanthus amarus and Andrographis paniculata, used in Ayurveda medicine in inhibiting SARS-CoV-2. 3 Biotech 2021; 11: 44 DOI: 10.1007/s13205-020-02578-7.

Crossref PubMed Google Scholar
139 Joshi T, Joshi T, Sharma P, Mathpal S, Pundir H, Bhatt V, Chandra S. In silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. Eur Rev Med Pharmacol Sci 2020; 24: 4529-4536 DOI: 10.26355/eurrev_202004_21036.

Crossref PubMed Google Scholar
140 Sekiou O, Bouziane I, Frissou N, Bouslama Z, Honcharova O, Djemel A, Benselhoub A. In-Silico identification of potent inhibitors of COVID-19 main protease (Mpro) from natural products. Int J Biochem Physiol 2021; 5: 000189 DOI: 10.23880/ijbp-16000189.

Crossref PubMed Google Scholar
141 Alimohammadi SZM, Hasani KM, Malekahmadi M, Persad E, Heshmati J. The effect of quercetin supplementation on clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. Food Sci Nutr 2023; DOI: 10.1002/fsn3.3715.

Crossref PubMed Google Scholar
142 Gangarapu K, Loganathan K, Devi MSS, Parameswaran S, Kanakavalli K, Kumar KM, Kumar D. In Silico computational screening of Kabasura Kudineer – official Siddha formulation and JACOM against SARS-CoV-2 spike protein. J Ayurveda Integr Med 2020; 13: 100324 DOI: 10.1016/j.jaim.2020.05.009.

Crossref PubMed Google Scholar
143 Vijayakumar B, Ramesh D, Joji A, Jayachandra Prakasan J, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020; 886: 173448 DOI: 10.1016/j.ejphar.2020.173448.

Crossref PubMed Google Scholar
144 Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity. J Agric Food Chem 2020; 68: 13982-13989 DOI: 10.1021/acs.jafc.0c05064.

Crossref PubMed Google Scholar
145 da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. Essential oils as antiviral agents. Potential of essential oils to treat SARS−COV−2 infection: An in−silico investigation. Int J Mol Sci 2020; 21: 1-37 DOI: 10.3390/ijms21103426.

Crossref PubMed Google Scholar
146 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: An in silico study for drug development. J Biomol Struct Dyn 2020; 39: 6306-6316 DOI: 10.1080/07391102.2020.1796811.

Crossref PubMed Google Scholar
147 Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 2020; 11: 1-11 DOI: 10.3389/fimmu.2020.01451.

Crossref PubMed Google Scholar
148 Mbikay M, Chrétien M. Isoquercetin as an anti-COVID-19 medication: A potential to realize. Front Pharmacol 2022; 13: 1-13 DOI: 10.3389/fphar.2022.830205.

Crossref PubMed Google Scholar
149 Fiorani M, Accorsi A, Cantoni O. Human red blood cells as a natural flavonoid reservoir. Free Radic Res 2003; 37: 1331-1338 DOI: 10.1080/10715760310001615998.

Crossref PubMed Google Scholar
150 Guo Y, Mah E, Bruno RS. Quercetin bioavailability is associated with inadequate plasma vitamin C status and greater plasma endotoxin in adults. Nutrition 2014; 30: 1279-1286 DOI: 10.1016/j.nut.2014.03.032.

Crossref PubMed Google Scholar
151 Martini S, Bonechi C, Rossi C. Interaction of quercetin and its conjugate quercetin 3-O-β-D-glucopyranoside with albumin as determined by NMR relaxation data. J Nat Prod 2008; 71: 175-178 DOI: 10.1021/np070285u.

Crossref PubMed Google Scholar
152 Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2017; 2: e89373 DOI: 10.1172/jci.insight.89373.

Crossref PubMed Google Scholar
153 Fiorani M, De Sanctis R, De Bellis R, Dachà M. Intracellular flavonoids as electron donors for extracellular ferricyanide reduction in human erythrocytes. Free Radic Biol Med 2002; 32: 64-72 DOI: 10.1016/S0891-5849(01)00762-6.

Crossref PubMed Google Scholar
154 Terao J, Murota K, Kawai Y. Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo . Food Funct 2011; 2: 11-17 DOI: 10.1039/C0FO00106F.

Crossref PubMed Google Scholar
155 Gong G, Guan YY, Zhang ZL, Rahman K, Wang SJ, Zhou S, Luan X, Zhang H. Isorhamnetin: a review of pharmacological effects. Biomed Pharmacother 2020; 128: 110301 DOI: 10.1016/j.biopha.2020.110301.

Crossref PubMed Google Scholar
156 Fan D, Zhou X, Zhao C, Chen H, Zhao Y, Gong X. Anti-inflammatory, antiviral and quantitative study of quercetin-3-O-β-D-glucuronide in Polygonum perfoliatum L. Fitoterapia 2011; 82: 805-810 DOI: 10.1016/j.fitote.2011.04.007.

Crossref PubMed Google Scholar
157 Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, Bilia A, Efferth T, Schwarz W. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med 2014; 80: 177-182 DOI: 10.1055/s-0033-1360277.

Artikel in Thieme Connect PubMed Google Scholar
158 Shaldam MA, Yahya G, Mohamed NH, Abdel-Daim MM, Al Naggar Y. In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes. Environ Sci Pollut Res Int 2021; 28: 40507-40514 DOI: 10.1007/s11356-021-14195-9.

Crossref PubMed Google Scholar
159 Saeed M, Naveed M, Arif M, Kakar M, Manzoor R, El-Hack M, Alagawany M, Tiwari R, Khandia R, Munjal A, Karthik K, Dhama K, Iqbal H, Dadar M, Sun C. Green tea (Camellia sinensis) andl-theanine: Medicinal values and beneficial applications in humans – a comprehensive review. Biomed Pharmacother 2017; 95: 1260-1275 DOI: 10.1016/j.biopha.2017.09.024.

Crossref PubMed Google Scholar
160 Jena A, Kanungo N, Nayak V, Chainy G, Dandapat J. Catechin and curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: insights from computational study and implication for intervention. 2020; 11: 2043 DOI: 10.21203/rs.3.rs-22057/v1.

Crossref PubMed Google Scholar
161 Henss L, Auste A, Schürmann C, Schmidt C, von Rhein C, Mühlebach MD, Schnierle BS. The green tea catechin epigallocatechin gallate inhibits SARS-CoV- 2 infection. J Gen Virol 2021; 102: 001574 DOI: 10.1099/jgv.0.001574.

Crossref PubMed Google Scholar
162 Mishra CB, Pandey P, Sharma RD, Malik MZ, Mongre RK, Lynn AM, Prasad R, Jeon R, Prakash A. Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: An integrated computational approach. Brief Bioinform 2021; 22: 1346-1360 DOI: 10.1093/bib/bbaa378.

Crossref PubMed Google Scholar
163 Mhatre S, Gurav N, Shah M, Patravale V. Entry-inhibitory role of catechins against SARS-CoV-2 and its UK variant. Comput Biol Med 2021; 135: 104560 DOI: 10.1016/j.compbiomed.2021.104560.

Crossref PubMed Google Scholar
164 Rabezanahary H, Badr A, Checkmahomed L, Pageau K, Desjardins Y, Baz M. Epigallocatechin gallate and isoquercetin synergize with remdesivir to reduce SARS-COV-2 replication in vitro . Front Virol 2022; 2: 1-9 DOI: 10.3389/fviro.2022.956113.

Crossref PubMed Google Scholar
165 Koch E. Previfenon® as Chemoprophylaxis of COVID-19 in Health Workers – full text view. Accessed 06.11.2023 at: https://clinicaltrials.gov/ct2/show/NCT04446065

PubMed Google Scholar
166 Song JW, Long JY, Xie L, Zhang LL, Xie QX, Chen HJ, Deng M, Li XF. Applications, phytochemistry, pharmacological effects, pharmacokinetics, toxicity of Scutellaria baicalensis Georgi. and its probably potential therapeutic effects on COVID-19: A review. Chinese Med (United Kingdom) 2020; 15: 1-26 DOI: 10.1186/s13020-020-00384-0.

Crossref PubMed Google Scholar
167 Zhao Y, Chen XY, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull 2016; 61: 1391-1398 DOI: 10.1007/s11434-016-1136-5.

Crossref PubMed Google Scholar
168 Li Y, Song K, Zhang H, Yuan M, An N, Wei Y, Wang L, Sun Y, Xing Y, Gao Y. Anti-inflammatory and immunomodulatory effects of baicalin in cerebrovascular and neurological disorders. Brain Res Bull 2020; 164: 314-324 DOI: 10.1016/j.brainresbull.2020.08.016.

Crossref PubMed Google Scholar
169 Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, Lan S, Slack RL, Kirby KA, Bassit L, Amblard F, Kim B, AbuBakar S, Sarafianos SG, Schinazi RF. Baicalein and baicalin inhibit SARS-CoV-2 RNA-Dependent-RNA polymerase. Microorganisms 2021; 9: 893 DOI: 10.3390/microorganisms9050893.

Crossref PubMed Google Scholar
170 Liu H, Ye F, Sun Q, Liang H, Li C, Li S, Lu R, Huang B, Tan W, Lai L. Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro . J Enzyme Inhib Med Chem 2021; 36: 497-503 DOI: 10.1080/14756366.2021.1873977.

Crossref PubMed Google Scholar
171 Huang S, Liu Y, Zhang Y, Zhang R, Zhu CJ, Fan L, Pei G, Zhang B, Shi Y. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduct Target Ther 2020; 5: 266 DOI: 10.1038/s41392-020-00353-x.

Crossref PubMed Google Scholar
172 Su HX, Yao S, Zhao WF, Li MJ, Liu J, Shang WJ, Xie H, Ke CQ, Hu HC, Gao MN, Yu KQ, Liu H, Shen JS, Tang W, Zhang LK, Xiao GF, Ni L, Wang DW, Zuo JP, Jiang HL, Bai F, Wu Y, Ye Y, Xu YC. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol Sin 2020; 41: 1167-1177 DOI: 10.1038/s41401-020-0483-6.

Crossref PubMed Google Scholar
173 Jo S, Kim S, Kim D, Kim MS, Shin D. Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro. J Enzyme Inhib Med Chem 2020; 35: 1539-1544 DOI: 10.1080/14756366.2020.1801672.

Crossref PubMed Google Scholar
174 Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001; 49: 3106-3112 DOI: 10.1021/jf000892m.

Crossref PubMed Google Scholar
175 Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother 2008; 62: 437-441 DOI: 10.1093/jac/dkn243.

Crossref PubMed Google Scholar
176 Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, Zhang H, Luo H, Zhu L, Jiang P, Chen L, Shen Y, Luo M, Zuo G, Hu J, Duan D, Nie Y, Shi X, Wang W, Han Y, Li T, Liu Y, Ding M, Deng H, Xu X. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004; 78: 11334-11339 DOI: 10.1128/JVI.78.20.11334-11339.2004.

Crossref PubMed Google Scholar
177 Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease 2020; 31: 179-193 DOI: 10.1007/s13337-020-00598-8.

Crossref PubMed Google Scholar
178 Xie YZ, Peng CW, Su ZQ, Huang HT, Liu XH, Zhan SF, Huang XF. A practical strategy for exploring the pharmacological mechanism of luteolin against COVID-19/asthma comorbidity: Findings of system pharmacology and bioinformatics analysis. Front Immunol 2022; 12: 1-18 DOI: 10.3389/fimmu.2021.769011.

Crossref PubMed Google Scholar
179 Di Stadio A, DʼAscanio L, Vaira LA, Cantone E, De Luca P, Cingolani C, Motta G, De Riu G, Vitelli F, Spriano G, De Vincentiis M, Camaioni A, La Mantia I, Ferreli F, Brenner MJ. Ultramicronized palmitoylethanolamide and luteolin supplement combined with olfactory training to treat post-COVID-19 olfactory impairment: A multi-center double-blinded randomized placebo- controlled clinical trial. Curr Neuropharmacol 2022; 20: 2001-2012 DOI: 10.2174/1570159x20666220420113513.

Crossref PubMed Google Scholar
180 Yu R, Chen L, Lan R, Shen R, Li P. Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking. Int J Antimicrob Agents 2020; 56: 106012 DOI: 10.1016/j.ijantimicag.2020.106012.

Crossref PubMed Google Scholar
181 Shadrack DM, Deogratias G, Kiruri LW, Onoka I, Vianney JM, Swai H, Nyandoro SS. Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics. J Mol Model 2021; 27: 221 DOI: 10.1007/s00894-021-04833-x.

Crossref PubMed Google Scholar
182 Españo E, Kim J, Lee K, Kim JK. Phytochemicals for the treatment of COVID-19. J Microbiol 2021; 59: 959-977 DOI: 10.1007/s12275-021-1467-z.

Crossref PubMed Google Scholar
183 Aniszewski T. Alkaloids – secrets of life. Amsterdam: Elsevier Science; 2007: 1-59

Google Scholar
184 Schmeller T, Latz-Brüning B, Wink M. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 1997; 44: 257-266 DOI: 10.1016/S0031-9422(96)00545-6.

Crossref PubMed Google Scholar
185 Wink M, Schimmer O. Modes of Action of Defensive Secondary Metabolites. In: Roberts JA. ed. Annual Plant Reviews Online. Hoboken: John Wiley & Sons; 2018: 21-161

Google Scholar
186 Wink M, Schmeller T, Latz-Brüning B. Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA, and other molecular targets. J Chem Ecol 1998; 24: 1881-1937.: DOI: 10.1023/A1022315802264.

Crossref PubMed Google Scholar
187 Wink M. Chapter 1 molecular modes of action of cytotoxic alkaloids: From DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance. Alkaloids Chem Biol 2007; 64: 1-47 DOI: 10.1016/S1099-4831(07)64001-2.

Crossref PubMed Google Scholar
188 Li S, Chen C, Zhang H, Guo H, Wang H, Wang L, Zhang X, Hua S, Yu J, Xiao P. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67: 18-23 DOI: 10.1016/j.antiviral.2005.02.007.

Crossref PubMed Google Scholar
189 Alfaro M, Alfaro I, Angel C. Identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthus porrigens: a molecular docking study. Chem Phys Lett 2020; 761: 138068 DOI: 10.1016/j.cplett.2020.138068.

Crossref PubMed Google Scholar
190 Borquaye L, Gasu E, Boadu G, Kyei L, Amarh M, Mensah C, Nartey D, Commodore M, Adomako A, Acheampong P, Mensah J, Mormor D. Alkaloids from Cryptolepis sanguinolenta as potential inhibitors of SARS-CoV-2 viral proteins: An in silico study. Biomed Res Int 2020; 2020: 1-14 DOI: 10.1155/2020/5324560.

Crossref PubMed Google Scholar
191 Kar P, Kumar V, Balachandar V, Sen A, Jaishee N, Anandraj A, Malhotra H, Bhattacharyya S, Mukhopadhyay S, Kinoshita M, Govindasami V, Roy A, Naidoo D, Subramaniam MD. Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: A computational investigation. J Biomol Struct Dyn 2020; 40: 4532-4542 DOI: 10.1080/07391102.2020.1860133.

Crossref PubMed Google Scholar
192 Garg S, Roy A. In silico analysis of selected alkaloids against main protease (Mpro) of SARS-CoV-2. Chem Biol Interact 2020; 332: 109309 DOI: 10.1016/j.cbi.2020.109309.

Crossref PubMed Google Scholar
193 Karatza E, Ismailos G, Karalis V. Colchicine for the treatment of COVID-19 patients: Efficacy, safety, and model informed dosage regimens. Xenobiotica 2021; 51: 643-656 DOI: 10.1080/00498254.2021.1909782.

Crossref PubMed Google Scholar
194 U. S. Food and Drug Administration. Colchicine (marketed as Colcrys) Information. Accessed March 9, 2023 at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/colchicine-marketed-colcrys-information

PubMed Google Scholar
195 Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241 DOI: 10.1038/nature04516.

Crossref PubMed Google Scholar
196 Marques-da-Silva C, Chaves MM, Castro NG, Coutinho-Silva R, Guimaraes MZP. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: Implications for its therapeutic action. Br J Pharmacol 2011; 163: 912-926 DOI: 10.1111/j.1476-5381.2011.01254.x.

Crossref PubMed Google Scholar
197 Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res 2020; 126: 1260-1280 DOI: 10.1161/CIRCRESAHA.120.315937.

Crossref PubMed Google Scholar
198 Drosos AA, Pelechas E, Drossou V, Voulgari PV. Colchicine against SARS-CoV-2 infection: What is the evidence?. Rheumatol Ther 2022; 9: 379-389 DOI: 10.1007/s40744-022-00425-0.

Crossref PubMed Google Scholar
199 Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, Metallidis S, Sianos G, Baltagiannis S, Panagopoulos P, Dolianitis K, Randou E, Syrigos K, Kotanidou A, Koulouris NG, Milionis H, Sipsas N, Gogos C, Tsoukalas G, Olympios CD, Tsagalou E, Migdalis I, Gerakari S, Angelidis C, Alexopoulos D, Davlouros P, Hahalis G, Kanonidis I, Katritsis D, Kolettis T, Manolis AS, Michalis L, Naka KK, Pyrgakis VN, Toutouzas KP, Triposkiadis F, Tsioufis K, Vavouranakis E, Martinèz-Dolz L, Reimers B, Stefanini GG, Cleman M, Goudevenos J, Tsiodras S, Tousoulis D, Iliodromitis E, Mehran R, Dangas G, Stefanadis C. GRECCO-19 investigators. Effect of colchicine vs. standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: The GRECCO-19 randomized clinical trial. JAMA Netw Open 2020; 3: e2013136 DOI: 10.1001/jamanetworkopen.2020.13136.

Crossref PubMed Google Scholar
200 Brunetti L, Diawara O, Tsai A, Firestein BL, Nahass RG, Poiani G, Schlesinger N. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med 2020; 9: 2961 DOI: 10.3390/jcm9092961.

Crossref PubMed Google Scholar
201 Della-Torre E, Della-Torre F, Kusanovic M, Scotti R, Ramirez GA, Dagna L, Tresoldi M. Treating COVID-19 with colchicine in community healthcare setting. Clin Immunol 2020; 217: 108490 DOI: 10.1016/j.clim.2020.108490.

Crossref PubMed Google Scholar
202 Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, Gigante SL, Benatti MN, Rezek UC, Emrich-Filho LL, Sousa BAA, Almeida SCL, Luppino Assad R, Veras FP, Schneider A, Rodrigues TS, Leiria LOS, Cunha LD, Alves-Filho JC, Cunha TM, Arruda E, Miranda CH, Pazin-Filho A, Auxiliadora-Martins M, Borges MC, Fonseca BAL, Bollela VR, Del-Ben CM, Cunha FQ, Zamboni DS, Santana RC, Vilar FC, Louzada-Junior P, Oliveira RDR. Beneficial effects of colchicine for moderate to severe COVID-19: A randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021; 7: e001455 DOI: 10.1136/rmdopen-2020-001455.

Crossref PubMed Google Scholar
203 Manenti L, Maggiore U, Fiaccadori E, Meschi T, Antoni AD, Nouvenne A, Ticinesi A, Cerundolo N, Prati B, Delsante M, Gandoflini I, Donghi L, Gentile M, Farina MT, Oliva V, Zambrano C, Regolisti G, Palmisano A, Caminiti C, Cocchi E, Ferrari C, Riella LV, Cravedi P, Peruzzi L. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021; 16: e0248276 DOI: 10.1371/journal.pone.0248276.

Crossref PubMed Google Scholar
204 Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol 2020; 2020: 8865954 DOI: 10.1155/2020/8865954.

Crossref PubMed Google Scholar
205 Scarsi M, Piantoni S, Colombo E, Airó P, Richini D, Miclini M, Bertasi V, Bianchi M, Bottone D, Civelli P, Cotelli MS, Damiolini E, Galbassini G, Gatta D, Ghirardelli ML, Magri R, Malamani P, Mendeni M, Molinari S, Morotti A, Salada L, Turla M, Vender A, Tincani A, Brucato A, Franceschini F, Furloni R, Andreoli L. Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome. Ann Rheum Dis 2020; 79: 1286-1289 DOI: 10.1136/annrheumdis-2020-217712.

Crossref PubMed Google Scholar
206 Tardif JC, Bouabdallaoui N, LʼAllier PL, Gaudet D, Shah B, Pillinger MH, Lopez-Sendon J, da Luz P, Verret L, Audet S, Dupuis J, Denault A, Pelletier M, Tessier PA, Samson S, Fortin D, Tardif JD, Busseuil D, Goulet E, Lacoste C, Dubois A, Joshi AY, Waters DD, Hsue P, Lepor NE, Lesage F, Sainturet N, Roy-Clavel E, Bassevitch Z, Orfanos A, Stamatescu G, Grégoire JC, Busque L, Lavallée C, Hétu PO, Paquette JS, Deftereos SG, Levesque S, Cossette M, Nozza A, Chabot-Blanchet M, Dubé MP, Guertin MC, Boivin G. COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med 2021; 9: 924-932 DOI: 10.1016/S2213-2600(21)00222-8.

Crossref PubMed Google Scholar
207 Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet Respir Med 2021; 9: 1419-1426 DOI: 10.1016/S2213-2600(21)00435-5.

Crossref PubMed Google Scholar
208 Kamran S, Sinniah A, Abdulghani MAM, Alshawsh MA. Therapeutic potential of certain terpenoids as anticancer agents: a scoping review. Cancers (Basel) 2022; 14: 1100 DOI: 10.3390/cancers14051100.

Crossref PubMed Google Scholar
209 Kulkarni S, Nagarajan SK, Ramesh V, Palaniyandi V, Sellamuthu P, Madhavan T. Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein. J Mol Struct 2020; 1221: 128823 DOI: 10.1016/j.molstruc.2020.128823.

Crossref PubMed Google Scholar
210 Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, Finamore C, Bozza S, Francisci D, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain. Front Chem 2020; 8: 1-15 DOI: 10.3389/fchem.2020.572885.

Crossref PubMed Google Scholar
211 Singh S, Florez H. Bioinformatic study to discover natural molecules with activity against COVID-19. F1000Res 2020; 9: 1203 DOI: 10.12688/f1000research.26731.1.

Crossref PubMed Google Scholar
212 Malekmohammad K, Rafieian-Kopaei M. Mechanistic aspects of medicinal plants and secondary metabolites against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Curr Pharm Des 2021; 27: 3996-4007 DOI: 10.2174/1381612827666210705160130.

Crossref PubMed Google Scholar
213 Chikhale R, Gurav S, Patil DR, Sinha DS, Prasad DS, Shakya A, Shrivastava S, Gurav N, Prasad R. Sars-CoV-2 host entry and replication inhibitors from Indian ginseng: An in-silico approach. J Biomol Struct Dyn 2020; 39: 4510-4521 DOI: 10.1080/07391102.2020.1778539.

Crossref PubMed Google Scholar
214 Siddiqui S, Upadhyay S, Ahmad R, Gupta A, Srivastava A, Trivedi A, Husain I, Ahmad B, Ahamed M, Khan MA. Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment. J Biomol Struct Dyn 2022; 40: 3928-3948 DOI: 10.1080/07391102.2020.1852117.

Crossref PubMed Google Scholar
215 Diniz LRL, Perez-Castillo Y, Elshabrawy HA, Filho CSMB, de Sousa DP. Bioactive terpenes and their derivatives as potential SARS-CoV-2 proteases inhibitors from molecular modeling studies. Biomolecules 2021; 11: 74 DOI: 10.3390/biom11010074.

Crossref PubMed Google Scholar
216 Giofrè SV, Napoli E, Iraci N, Speciale A, Cimino F, Muscarà C, Molonia MS, Ruberto G, Saija A. Interaction of selected terpenoids with two SARS-CoV-2 key therapeutic targets: An in silico study through molecular docking and dynamics simulations. Comput Biol Med 2021; 134: 104538 DOI: 10.1016/j.compbiomed.2021.104538.

Crossref PubMed Google Scholar
217 Park JY, Kim JH, Kim Y, Jeong H, Kim D, Park K, Kwon HJ, Park SC, Lee W, Ryu Y. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem 2012; 20: 5928-5935 DOI: 10.1016/j.bmc.2012.07.038.

Crossref PubMed Google Scholar
218 Falade VA, Adelusi TI, Adedotun IO, Abdul-Hammed M, Lawal TA, Agboluaje SA. In silico investigation of saponins and tannins as potential inhibitors of SARS-CoV-2 main protease (Mpro). Silico Pharmacol 2021; 9: 1-15 DOI: 10.1007/s40203-020-00071-w.

Crossref PubMed Google Scholar
219 Sun H, Xie Y, Ye YP. Advances in saponin-based adjuvants. Vaccine 2009; 27: 1787-1796 DOI: 10.1016/j.vaccine.2009.01.091.

Crossref PubMed Google Scholar
220 Skene CD, Sutton P. Saponin-adjuvanted particulate vaccines for clinical use. Methods 2006; 40: 53-59 DOI: 10.1016/j.ymeth.2006.05.019.

Crossref PubMed Google Scholar
221 Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr H. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045-2046 DOI: 10.1016/S0140-6736(03)13615-X.

Crossref PubMed Google Scholar
222 He MF, Liang JH, Shen YN, Zhang JW, Liu Y, Yang KY, Liu LC, Wang J, Xie Q, Hu C, Song X, Wang Y. Glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2. Life 2022; 12: 1706 DOI: 10.3390/life12111706.

Crossref PubMed Google Scholar
223 Behl T, Rocchetti G, Chadha S, Zengin G, Bungau S, Kumar A, Mehta V, Uddin MS, Khullar G, Setia D, Arora S, Sinan KI, Ak G, Putnik P, Gallo M, Montesano D. Phytochemicals from plant foods as potential source of antiviral agents: An overview. Pharmaceuticals 2021; 14: 1-46 DOI: 10.3390/ph14040381.

Crossref PubMed Google Scholar
224 Khalifa I, Zhu W, Mohammed HHH, Dutta K, Li C. Tannins inhibit SARS-CoV-2 through binding with catalytic dyad residues of 3CLpro: An in silico approach with 19 structural different hydrolysable tannins. J Food Biochem 2020; 44: 1-19 DOI: 10.1111/jfbc.13432.

Crossref PubMed Google Scholar
225 Wang SC, Chen Y, Wang YC, Wang WJ, Yang CS, Tsai CL, Hou MH, Chen HF, Shen YC, Hung MC. Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease. Am J Cancer Res 2020; 10: 4538-4546

PubMed Google Scholar
226 Zhang YN, Zhang QY, Li XD, Xiong J, Xiao SQ, Wang Z, Zhang ZR, Deng CL, Yang XL, Wei HP, Yuan ZM, Ye HQ, Zhang B. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect 2020; 9: 1170-1173 DOI: 10.1080/22221751.2020.1772676.

Crossref PubMed Google Scholar
227 He CL, Huang LY, Wang K, Gu CJ, Hu J, Zhang GJ, Xu W, Xie YH, Tang N, Huang AL. Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products. Signal Transduct Target Ther 2021; 6: 2020-2022 DOI: 10.1038/s41392-021-00531-5.

Crossref PubMed Google Scholar
228 Jan JT, Cheng TJR, Juang YP, Ma HH, Wu YT, Yang WB, Cheng CW, Chen X, Chou TH, Shie JJ, Cheng WC, Chein RJ, Mao SS, Liang PH, Ma C, Hung SC, Wong CH. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A 2021; 118: 1-8 DOI: 10.1073/pnas.2021579118.

Crossref PubMed Google Scholar
229 Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, Shirai T, Kanaya S, Ito Y, Kim KS, Nomura T, Suzuki T, Nishioka K, Ando S, Ejima K, Koizumi Y, Tanaka T, Aoki S, Kuramochi K, Suzuki T, Hashiguchi T, Maenaka K, Matano T, Muramatsu M, Saijo M, Aihara K, Iwami S, Takeda M, McKeating JA, Wakita T. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience 2021; 24: 102367 DOI: 10.1016/j.isci.2021.102367.

Crossref PubMed Google Scholar
230 Varghese FS, van Woudenbergh E, Overheul GJ, Eleveld MJ, Kurver L, van Heerbeek N, van Laarhoven A, Miesen P, den Hartog G, de Jonge MI, van Rij RP. Berberine and obatoclax inhibit SARS-Cov-2 replication in primary human nasal epithelial cells in vitro . Viruses 2021; 13: 282 DOI: 10.3390/v13020282.

Crossref PubMed Google Scholar
231 Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res 2020; 181: 104878 DOI: 10.1016/j.antiviral.2020.104878.

Crossref PubMed Google Scholar
232 Xia B, Shen X, He Y, Pan X, Liu FL, Wang Y, Yang F, Fang S, Wu Y, Duan Z, Zuo X, Xie Z, Jiang X, Xu L, Chi H, Li S, Meng Q, Zhou H, Zhou Y, Cheng X, Xin X, Jin L, Zhang HL, Yu DD, Li MH, Feng XL, Chen J, Jiang H, Xiao G, Zheng YT, Zhang LK, Shen J, Li J, Gao Z. SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target. Cell Res 2021; 31: 847-860 DOI: 10.1038/s41422-021-00519-4.

Crossref PubMed Google Scholar
233 Huang L, Yuen TTT, Ye Z, Liu S, Zhang G, Chu H, Yue J. Berbamine inhibits SARS-CoV-2 infection by compromising TRPMLs-mediated endolysosomal trafficking of ACE2. Signal Transduct Target Ther 2021; 6: 168 DOI: 10.1038/s41392-021-00584-6.

Crossref PubMed Google Scholar
234 Gyebi GA, Ogunro OB, Adegunloye AP, Ogunyemi OM, Afolabi SO. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): An in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn 2021; 39: 3396-3408 DOI: 10.1080/07391102.2020.1764868.

Crossref PubMed Google Scholar
235 Yang Y, Yang P, Huang C, Wu Y, Zhou Z, Wang X, Wang S. Inhibitory effect on SARS-CoV-2 infection of neferine by blocking Ca(2+) -dependent membrane fusion. J Med Virol 2021; 93: 5825-5832 DOI: 10.1002/jmv.27117.

Crossref PubMed Google Scholar
236 Choy KT, Wong AYL, Kaewpreedee P, Sia SF, Chen D, Hui KPY, Chu DKW, Chan MCW, Cheung PPH, Huang X, Peiris M, Yen HL. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro . Antiviral Res 2020; 178: 104786 DOI: 10.1016/j.antiviral.2020.104786.

Crossref PubMed Google Scholar
237 Ku KB, Shin HJ, Kim HS, Kim BT, Kim SJ, Kim C. Repurposing screens of FDA-approved drugs identify 29 inhibitors of SARS-CoV-2. J Microbiol Biotechnol 2020; 30: 1843-1853 DOI: 10.4014/JMB.2009.09009.

Crossref PubMed Google Scholar
238 Tsai YC, Lee CL, Yen HR, Chang YS, Lin YP, Huang SH, Lin CW. Antiviral action of tryptanthrin isolated from Strobilanthes cusia leaf against human coronavirus nl63. Biomolecules 2020; 10: 366 DOI: 10.3390/biom10030366.

Crossref PubMed Google Scholar
239 Fan S, Zhen Q, Chen C, Wang W, Wu Q, Ma H, Zhang C, Zhang L, Lu B, Ge H, Yong L, Li B, Yu Y, Chen W, Mao Y, Qu G, Su L, Wang A, Ding Z, Li H, Zhang J, Wang Y, Gao Y, Xu X, Zhu Z, Chen J, Zhang L, Liang H, Wu S, Huang M, Xia Q, Li P, Sun Y, Liang C, Wei W, Liu Q, Sun L. Clinical efficacy of low-dose emetine for patients with COVID-19: A real-world study. J bio-X Res 2021; 4: 53-59 DOI: 10.1097/JBR.0000000000000076.

Crossref PubMed Google Scholar
240 Kumar R, Afsar M, Khandelwal N, Chander Y, Riyesh T, Kumar R, Gulati BR, Pal Y, Barua S, Tripathi BN, Hussain T, Kumar N. Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E. Antiviral Res 2021; 189: 105056 DOI: 10.1016/j.antiviral.2021.105056.

Crossref PubMed Google Scholar
241 Wang A, Sun Y, Liu Q, Wu H, Liu J, He J, Yu J, Chen QQ, Ge Y, Zhang Z, Hu C, Chen C, Qi Z, Zou F, Liu F, Hu J, Zhao M, Huang T, Wang B, Wang L, Wang W, Wang W, Ren T, Liu J, Sun Y, Fan S, Wu Q, Liang C, Sun L, Su B, Wei W, Liu Q. Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences. Mol Biomed 2020; 1: 14 DOI: 10.1186/s43556-020-00018-9.

Crossref PubMed Google Scholar
242 Shree P, Mishra P, Selvaraj C, Singh SK, Chaube R, Garg N, Tripathi YB. Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of Ayurvedic medicinal plants – Withania somnifera (ashwagandha), Tinospora cordifolia (giloy) and Ocimum sanctum (tulsi) – a molecular docking study. J Biomol Struct Dyn 2022; 40: 190-203 DOI: 10.1080/07391102.2020.1810778.

Crossref PubMed Google Scholar
243 Mohammadi S, Heidarizadeh M, Entesari M, Esmailpour A, Esmailpour M, Moradi R, Sakhaee N, Doustkhah E. In silico investigation on the inhibiting role of nicotine/caffeine by blocking the S protein of SARS-CoV-2 versus ACE2 receptor. Microorganisms 2020; 8: 1600 DOI: 10.3390/microorganisms8101600.

Crossref PubMed Google Scholar
244 Elzupir AO. Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2. J Biomol Struct Dyn 2022; 40: 2113-2120 DOI: 10.1080/07391102.2020.1835732.

Crossref PubMed Google Scholar
245 Yang CW, Lee YZ, Hsu HY, Shih C, Chao YS, Chang HY, Lee SJ. Targeting coronaviral replication and cellular JAK2 mediated dominant NF-κB activation for comprehensive and ultimate inhibition of coronaviral activity. Sci Rep 2017; 7: 4105 DOI: 10.1038/s41598-017-04203-9.

Crossref PubMed Google Scholar
246 Yang CW, Lee YZ, Kang IJ, Barnard DL, Jan JT, Lin D, Huang CW, Yeh TK, Chao YS, Lee SJ. Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. Antiviral Res 2010; 88: 160-168 DOI: 10.1016/j.antiviral.2010.08.009.

Crossref PubMed Google Scholar
247 Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC, Chao PDL. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68: 36-42 DOI: 10.1016/j.antiviral.2005.07.002.

Crossref PubMed Google Scholar
248 Große M, Ruetalo N, Layer M, Hu D, Businger R, Rheber S, Setz C, Rauch P, Auth J, Fröba M, Brysch E, Schindler M, Schubert U. Quinine inhibits infection of human cell lines with SARS-CoV-2. Viruses 2021; 13: 647 DOI: 10.3390/v13040647.

Crossref PubMed Google Scholar
249 Clarke EC, Nofchissey RA, Ye C, Bradfute SB. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication. Glycobiology 2021; 31: 378-384 DOI: 10.1093/glycob/cwaa091.

Crossref PubMed Google Scholar
250 Raj V, Park JG, Cho KH, Choi P, Kim T, Ham J, Lee J. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. Int J Biol Macromol 2021; 168: 474-485 DOI: 10.1016/j.ijbiomac.2020.12.020.

Crossref PubMed Google Scholar
251 Nguyen LC, Yang D, Nicolaescu V, Best TJ, Gula H, Saxena D, Gabbard JD, Chen SN, Ohtsuki T, Friesen JB, Drayman N, Mohamed A, Dann C, Silva D, Robinson-Mailman L, Valdespino A, Stock L, Suárez E, Jones KA, Azizi SA, Demarco JK, Severson WE, Anderson CD, Millis JM, Dickinson BC, Tay S, Oakes SA, Pauli GF. Palmer KE; National COVID Cohort Collaborative Consortium, Meltzer DO, Randall G, Rosner MR. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv 2022; 8: eabi6110 DOI: 10.1126/sciadv.abi6110.

Crossref PubMed Google Scholar
252 van Breemen RB, Muchiri RN, Bates TA, Weinstein JB, Leier HC, Farley S, Tafesse FG. Cannabinoids block cellular entry of SARS-CoV-2 and the emerging variants. J Nat Prod 2022; 85: 176-184 DOI: 10.1021/acs.jnatprod.1c00946.

Crossref PubMed Google Scholar
253 Yang QY, Tian XY, Fang WS. Bioactive coumarins from Boenninghausenia sessilicarpa . J Asian Nat Prod Res 2007; 9: 59-65 DOI: 10.1080/10286020500382397.

Crossref PubMed Google Scholar
254 Cho JK, Curtis-Long MJ, Lee KH, Kim DW, Ryu HW, Yuk HJ, Park KH. Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa . Bioorganic Med Chem 2013; 21: 3051-3057 DOI: 10.1016/j.bmc.2013.03.027.

Crossref PubMed Google Scholar
255 Kim DW, Seo KH, Curtis-Long MJ, Oh KY, Oh JW, Cho JK, Lee KH, Park KH. Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia . J Enzyme Inhib Med Chem 2014; 29: 59-63 DOI: 10.3109/14756366.2012.753591.

Crossref PubMed Google Scholar
256 Park JY, Jeong HJ, Kim JH, Kim YM, Park SJ, Kim D, Park KH, Lee WS, Ryu YB. Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute respiratory syndrome coronavirus. Biol Pharm Bull 2012; 35: 2036-2042 DOI: 10.1248/bpb.b12-00623.

Crossref PubMed Google Scholar
257 Valizadeh H, Abdolmohammadi-Vahid S, Danshina S, Ziya Gencer M, Ammari A, Sadeghi A, Roshangar L, Aslani S, Esmaeilzadeh A, Ghaebi M, Valizadeh S, Ahmadi M. Nano-curcumin therapy, a promising method in modulating inflammatory cytokines in COVID-19 patients. Int Immunopharmacol 2020; 89: 107088 DOI: 10.1016/j.intimp.2020.107088.

Crossref PubMed Google Scholar
258 Pawar KS, Mastud RN, Pawar SK, Pawar SS, Bhoite RR, Bhoite RR, Kulkarni MV, Deshpande AR. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: A randomized clinical trial. Front Pharmacol 2021; 12: 669362 DOI: 10.3389/fphar.2021.669362.

Crossref PubMed Google Scholar
259 Goc A, Sumera W, Rath M, Niedzwiecki A. Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions. PLoS One 2021; 16: e0253489 DOI: 10.1371/journal.pone.0253489.

Crossref PubMed Google Scholar
260 Bormann M, Alt M, Schipper L, van de Sand L, Le-Trilling VTK, Rink L, Heinen N, Madel RJ, Otte M, Wuensch K, Heilingloh CS, Mueller T, Dittmer U, Elsner C, Pfaender S, Trilling M, Witzke O, Krawczyk A. Turmeric root and its bioactive ingredient curcumin effectively neutralize SARS-CoV-2 in vitro . Viruses 2021; 13: 1914 DOI: 10.3390/v13101914.

Crossref PubMed Google Scholar
261 Du R, Cooper L, Chen Z, Lee H, Rong L, Cui Q. Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro. Antiviral Res 2021; 190: 105075 DOI: 10.1016/j.antiviral.2021.105075.

Crossref PubMed Google Scholar
262 Tito A, Colantuono A, Pirone L, Pedone E, Intartaglia D, Giamundo G, Conte I, Vitaglione P, Apone F. Pomegranate peel extract as an inhibitor of SARS-CoV-2 spike binding to human ACE2 receptor (in vitro): A promising source of novel antiviral drugs. Front Chem 2021; 9: 638187 DOI: 10.3389/fchem.2021.638187.

Crossref PubMed Google Scholar
263 Nishimura H, Okamoto M, Dapat I, Katsumi M, Oshitani H. Inactivation of SARS-CoV-2 by catechins from green tea. Jpn J Infect Dis 2021; 74: 421-423 DOI: 10.7883/yoken.JJID.2020.902.

Crossref PubMed Google Scholar
264 Hong S, Seo SH, Woo SJ, Kwon Y, Song M, Ha NC. Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain. J Agric Food Chem 2021; 69: 5948-5954 DOI: 10.1021/acs.jafc.1c02050.

Crossref PubMed Google Scholar
265 Jang M, Park YI, Cha YE, Park R, Namkoong S, Lee JI, Park J. Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro . Evid Based Complement Alternat Med 2020; 2020: 1-7 DOI: 10.1155/2020/5630838.

Crossref PubMed Google Scholar
266 Ohgitani E, Shin-Ya M, Ichitani M, Kobayashi M, Takihara T, Kawamoto M, Kinugasa H, Mazda O. Significant inactivation of sars-cov-2 in vitro by a green tea catechin, a catechin-derivative, and black tea galloylated theaflavins. Molecules 2021; 26: 3572 DOI: 10.3390/molecules26123572.

Crossref PubMed Google Scholar
267 Park JY, Ko JA, Kim DW, Kim YM, Kwon HJ, Jeong HJ, Kim CY, Park KH, Lee WS, Ryu YB. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem 2016; 31: 23-30 DOI: 10.3109/14756366.2014.1003215.

Crossref PubMed Google Scholar
268 Kanjanasirirat P, Suksatu A, Manopwisedjaroen S, Munyoo B, Tuchinda P, Jearawuttanakul K, Seemakhan S, Charoensutthivarakul S, Wongtrakoongate P, Rangkasenee N, Pitiporn S, Waranuch N, Chabang N, Khemawoot P, Sa-Ngiamsuntorn K, Pewkliang Y, Thongsri P, Chutipongtanate S, Hongeng S, Borwornpinyo S, Thitithanyanont A. High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component panduratin A as anti-SARS-CoV-2 agents. Sci Rep 2020; 10: 1-12 DOI: 10.1038/s41598-020-77003-3.

Crossref PubMed Google Scholar
269 Abdallah HM, El-Halawany AM, Sirwi A, El-Araby AM, Mohamed GA, Ibrahim SRM, Koshak AE, Asfour HZ, Awan ZA, Elfaky MA. Repurposing of some natural product isolates as SARS-COV-2 main protease inhibitors via in vitro cell free and cell-based antiviral assessments and molecular modeling approaches. Pharmaceuticals (Basel) 2021; 14: 213 DOI: 10.3390/ph14030213.

Crossref PubMed Google Scholar
270 Clementi N, Scagnolari C, DʼAmore A, Palombi F, Criscuolo E, Frasca F, Pierangeli A, Mancini N, Antonelli G, Clementi M, Carpaneto A, Filippini A. Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro . Pharmacol Res 2021; 163: 12-15 DOI: 10.1016/j.phrs.2020.105255.

Crossref PubMed Google Scholar
271 Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem 2020; 35: 145-151 DOI: 10.1080/14756366.2019.1690480.

Crossref PubMed Google Scholar
272 Pitsillou E, Liang J, Ververis K, Lim KW, Hung A, Karagiannis TC. Identification of small molecule inhibitors of the deubiquitinating activity of the SARS-CoV-2 papain-like protease: in silico molecular docking studies and in vitro enzymatic activity assay. Front Chem 2020; 8: 623971 DOI: 10.3389/fchem.2020.623971.

Crossref PubMed Google Scholar
273 Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Reyburn HT, Rizzuti B, Velazquez-Campoy A. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromol 2020; 164: 1693-1703 DOI: 10.1016/j.ijbiomac.2020.07.235.

Crossref PubMed Google Scholar
274 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. J Biomol Struct Dyn 2020; 0: 1-11 DOI: 10.1080/07391102.2020.1796811.

Crossref PubMed Google Scholar
275 Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, Nguyen TTH, Park SJ, Chang JS, Park KH, Rho MC, Lee WS. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg Med Chem 2010; 18: 7940-7947 DOI: 10.1016/j.bmc.2010.09.035.

Crossref PubMed Google Scholar
276 Khan A, Wang H, Wang Y, Qiu J, Wei X, Peng S, Saleem S, Khan M, Ali S, Wei DQ. In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro). Phyther Res 2020; 35: 2841-2845 DOI: 10.1002/ptr.6998.

Crossref PubMed Google Scholar
277 Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, Keum YS, Jeong YJ. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett 2012; 22: 4049-4054 DOI: 10.1016/j.bmcl.2012.04.081.

Crossref PubMed Google Scholar
278 Su H, Yao S, Zhao W, Zhang Y, Liu J, Shao Q, Wang Q, Li M, Xie H, Shang W, Ke C, Feng L, Jiang X, Shen J, Xiao G, Jiang H, Zhang L, Ye Y, Xu Y. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun 2021; 12: 1-12 DOI: 10.1038/s41467-021-23751-3.

Crossref PubMed Google Scholar
279 Zhan Y, Ta W, Tang W, Hua R, Wang J, Wang C, Lu W. Potential antiviral activity of isorhamnetin against SARS-CoV-2 spike pseudotyped virus in vitro . Drug Dev Res 2021; 82: 1124-1130 DOI: 10.1002/ddr.21815.

Crossref PubMed Google Scholar
280 Ogunyemi OM, Gyebi GA, Elfiky AA, Afolabi SO, Ogunro OB, Adegunloye AP, Ibrahim IM. Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: an in silico perspective. Antivir Chem Chemother 2020; 28: 2040206620984076 DOI: 10.1177/2040206620984076.

Crossref PubMed Google Scholar
281 Armstrong LA, Lange SM, Cesare VD, Matthews SP, Nirujogi RS, Cole I, Hope A, Cunningham F, Toth R, Mukherjee R, Bojkova D, Gruber F, Gray D, Wyatt PG, Cinatl J, Dikic I, Davies P, Kulathu Y. Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. PLoS One 2021; 16: e0253364 DOI: 10.1371/journal.pone.0253364.

Crossref PubMed Google Scholar
282 Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007; 50: 4087-4095 DOI: 10.1021/jm070295s.

Crossref PubMed Google Scholar
283 Ma Q, Li R, Pan W, Huang W, Liu B, Xie Y, Wang Z, Li C, Jiang H, Huang J, Shi Y, Dai J, Zheng K, Li X, Hui M, Fu L, Yang Z. Phillyrin (KD-1) exerts anti-viral and anti-inflammatory activities against novel coronavirus (SARS-CoV-2) and human coronavirus 229E (HCoV-229E) by suppressing the nuclear factor kappa B (NF-κB) signaling pathway. Phytomedicine 2020; 78: 153296 DOI: 10.1016/j.phymed.2020.153296.

Crossref PubMed Google Scholar
284 Stefanik M, Strakova P, Haviernik J, Miller AD, Ruzek D, Eyer L. Antiviral activity of vacuolar ATPase blocker diphyllin against SARS-COV-2. Microorganisms 2021; 9: 1-10 DOI: 10.3390/microorganisms9030471.

Crossref PubMed Google Scholar
285 Chen Z, Cui Q, Cooper L, Zhang P, Lee H, Chen Z, Wang Y, Liu X, Rong L, Du R. Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases. Cell Biosci 2021; 11: 1-8 DOI: 10.1186/s13578-021-00564-x.

Crossref PubMed Google Scholar
286 El Gizawy HA, Boshra SA, Mostafa A, Mahmoud SH, Ismail MI, Alsfouk AA, Taher AT, Al-Karmalawy AA. Pimenta dioica (L.) merr. bioactive constituents exert anti-sars-cov-2 and anti-inflammatory activities: molecular docking and dynamics, in vitro, and in vivo studies. Molecules 2021; 26: 5844 DOI: 10.3390/molecules26195844.

Crossref PubMed Google Scholar
287 David AB, Diamant E, Dor E, Barnea A, Natan N, Levin L, Chapman S, Mimran LC, Epstein E, Zichel R, Torgeman A. Identification of SARS-CoV-2 receptor binding inhibitors by in vitro screening of drug libraries. Molecules 2021; 26: 1-12 DOI: 10.3390/molecules26113213.

Crossref PubMed Google Scholar
288 Rathinavel T, Palanisamy M, Palanisamy S, Subramanian A, Thangaswamy S. Phytochemical 6-gingerol – A promising drug of choice for COVID-19. Int J Adv Sci Eng 2020; 06: 1482-1489 DOI: 10.29294/ijase.6.4.2020.1482-1489.

Crossref PubMed Google Scholar
289 Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, Jochmans D, Leyssen P, Wang K, Neyts J, Yujie T, Blum G. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett 2021; 12: 1793-1802 DOI: 10.1021/acs.jpclett.0c03119.

Crossref PubMed Google Scholar
290 Pasquereau S, Nehme Z, Haidar Ahmad S, Daouad F, Van Assche J, Wallet C, Schwartz C, Rohr O, Morot-Bizot S, Herbein G. Resveratrol inhibits HCoV-229E and SARS-CoV-2 coronavirus replication in vitro . Viruses 2021; 13: 354 DOI: 10.3390/v13020354.

Crossref PubMed Google Scholar
291 Yang M, Wei J, Huang T, Lei L, Shen C, Lai J, Yang M, Liu L, Yang Y, Liu G, Liu Y. Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured Vero cells. Phyther Res 2021; 35: 1127-1129 DOI: 10.1002/ptr.6916.

Crossref PubMed Google Scholar
292 Ter Ellen BM, Kumar ND, Bouma EM, Troost B, van de Pol DPI, van der Ende-Metselaar HH, Apperloo L, van Gosliga D, van den Berge M, Nawijn MC, van der Voort PHJ, Moser J, Rodenhuis-Zybert IA, Smit JM. Resveratrol and pterostilbene inhibit SARS-CoV-2 replication in air–liquid interface cultured human primary bronchial epithelial cells. Viruses 2021; 13: 1335 DOI: 10.3390/v13071335.

Crossref PubMed Google Scholar
293 Pitsillou E, Liang J, Karagiannis C, Ververis K, Darmawan KK, Ng K, Hung A, Karagiannis TC. Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay. Comput Biol Chem 2020; 89: 107408 DOI: 10.1016/j.compbiolchem.2020.107408.

Crossref PubMed Google Scholar
294 Cao R, Hu H, Li Y, Wang X, Xu M, Liu J, Zhang H, Yan Y, Zhao L, Li W, Zhang T, Xiao D, Guo X, Li Y, Yang J, Hu Z, Wang M, Zhong W. Anti-SARS-CoV-2 potential of artemisinins in vitro . ACS Infect Dis 2020; 6: 2524-2531 DOI: 10.1021/acsinfecdis.0c00522.

Crossref PubMed Google Scholar
295 Nie C, Trimpert J, Moon S, Haag R, Gilmore K, Kaufer BB, Seeberger PH. In vitro efficacy of Artemisia extracts against SARS-CoV-2. Virol J 2021; 18: 1-7 DOI: 10.1186/s12985-021-01651-8.

Crossref PubMed Google Scholar
296 Nair MS, Huang Y, Fidock DA, Polyak SJ, Wagoner J, Towler MJ, Weathers PJ. Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. J Ethnopharmacol 2021; 274: 114016 DOI: 10.1016/j.jep.2021.114016.

Crossref PubMed Google Scholar
297 Zhou Y, Gilmore K, Ramirez S, Settels E, Gammeltoft KA, Pham LV, Fahnøe U, Feng S, Offersgaard A, Trimpert J, Bukh J, Osterrieder K, Gottwein JM, Seeberger PH. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci Rep 2021; 11: 14571 DOI: 10.1038/s41598-021-93361-y.

Crossref PubMed Google Scholar
298 Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, Zhang H, Yu W, Xu Q, Zou Y, Yuan Y, Guo J, Jin C, Guan X, Xie F, Song J. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomised and controlled trial. Int J Antimicrob Agents 2021; 57: 106216 DOI: 10.1016/j.ijantimicag.2020.106216.

Crossref PubMed Google Scholar
299 Sehailia M, Chemat S. Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: Potential repurposing of artenimol for COVID-19. J Biomol Struct Dyn 2021; 39: 6184-6194 DOI: 10.1080/07391102.2020.1796809.

Crossref PubMed Google Scholar
300 Lim CT, Tan KW, Wu M, Ulferts R, Armstrong LA, Ozono E, Drury LS, Milligan JC, Zeisner TU, Zeng J, Weissmann F, Canal B, Bineva-Todd G, Howell M, OʼReilly N, Beale R, Kulathu Y, Labib K, Diffley JFX. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease. Biochem J 2021; 478: 2517-2531 DOI: 10.1042/BCJ20210244.

Crossref PubMed Google Scholar
301 Zhao Y, Du X, Duan Y, Pan X, Sun Y, You T, Han L, Jin Z, Shang W, Yu J, Guo H, Liu Q, Wu Y, Peng C, Wang J, Zhu C, Yang X, Yang K, Lei Y, Guddat LW, Xu W, Xiao G, Sun L, Zhang L, Rao Z, Yang H. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell 2021; 12: 877-888 DOI: 10.1007/s13238-021-00836-9.

Crossref PubMed Google Scholar
302 Sa-Ngiamsuntorn K, Suksatu A, Pewkliang Y, Thongsri P, Kanjanasirirat P, Manopwisedjaroen S, Charoensutthivarakul S, Wongtrakoongate P, Pitiporn S, Chaopreecha J, Kongsomros S, Jearawuttanakul K, Wannalo W, Khemawoot P, Chutipongtanate S, Borwornpinyo S, Thitithanyanont A, Hongeng S. Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives. J Nat Prod 2021; 84: 1261-1270 DOI: 10.1021/acs.jnatprod.0c01324.

Crossref PubMed Google Scholar
303 Shi TH, Huang YL, Chen CC, Pi WC, Hsu YL, Lo LC, Chen WY, Fu SL, Lin CH. Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage. Biochem Biophys Res Commun 2020; 533: 467-473 DOI: 10.1016/j.bbrc.2020.08.086.

Crossref PubMed Google Scholar
304 Alhadrami HA, Sayed AM, Sharif AM, Azhar EI, Rateb ME. Olive-derived triterpenes suppress SARS-CoV-2 main protease: A promising scaffold for future therapeutics. Molecules 2021; 26: 2654 DOI: 10.3390/molecules26092654.

Crossref PubMed Google Scholar
305 Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, Park KH, Rho MC, Lee WS. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii . Bioorg Med Chem Lett 2010; 20: 1873-1876 DOI: 10.1016/j.bmcl.2010.01.152.

Crossref PubMed Google Scholar
306 van de Sand L, Bormann M, Alt M, Schipper L, Heilingloh CS, Steinmann E, Todt D, Dittmer U, Elsner C, Witzke O, Krawczyk A. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses 2021; 13: 1-10 DOI: 10.3390/v13040609.

Crossref PubMed Google Scholar
307 Srivastava V, Yadav A, Sarkar P. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc 2022; 49: 2999-3007 DOI: 10.1016/j.matpr.2020.10.055.

Crossref PubMed Google Scholar
308 Sinha SK, Shakya A, Prasad SK, Singh S, Gurav NS, Prasad RS, Gurav SS. An in-silico evaluation of different saikosaponins for their potency against SARS-CoV-2 using NSP15 and fusion spike glycoprotein as targets. J Biomol Struct Dyn 2020; 39: 1-12 DOI: 10.1080/07391102.2020.1762741.

Crossref PubMed Google Scholar
309 Kim TY, Jeon S, Jang Y, Gotina L, Won J, Ju YH, Kim S, Jang MW, Won W, Park MG, Pae AN, Han S, Kim S, Lee CJ. Platycodin D, a natural component of Platycodon grandiflorum, prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion. Exp Mol Med 2021; 53: 956-972 DOI: 10.1038/s12276-021-00624-9.

Crossref PubMed Google Scholar
310 Kumar S, Kashyap P, Chowdhury S, Kumar S, Panwar A, Kumar A. Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication. Phytomedicine 2021; 85: 153317 DOI: 10.1016/j.phymed.2020.153317.

Crossref PubMed Google Scholar
311 Cho J, Lee YJ, Kim JH, Kim SI, Kim SS, Choi BS, Choi JH. Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19. Sci Rep 2020; 10: 16200 DOI: 10.1038/s41598-020-72879-7.

Crossref PubMed Google Scholar
312 Song YH, Kim DW, Curtis-Long MJ, Yuk HJ, Wang Y, Zhuang N, Lee KH, Jeon KS, Park KH. Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits. Biol Pharm Bull 2014; 37: 1021-1028 DOI: 10.1248/bpb.b14-00026.

Crossref PubMed Google Scholar
313 Ahan RE, Hanifehnezhad A, Kehribar E, Oguzoglu TC, Földes K, Özçelik CE, Filazi N, Öztop S, Palaz F, Önder S, Bozkurt EU, Ergünay K, Özkul A, Şeker UÖŞ. A highly potent SARS-CoV-2 blocking lectin protein. ACS Infect Dis 2022; 8: 1253-1264 DOI: 10.1021/acsinfecdis.2c00006.

Crossref PubMed Google Scholar
314 Alsaidi S, Cornejal N, Mahoney O, Melo C, Verma N, Bonnaire T, Chang T, Oʼkeefe BR, Sailer J, Zydowsky TM, Teleshova N, Romero JAF. Griffithsin and carrageenan combination results in antiviral synergy against SARS-CoV-1 and 2 in a pseudoviral model. Mar Drugs 2021; 19: 1-8 DOI: 10.3390/md19080418.

Crossref PubMed Google Scholar
315 Cai Y, Xu W, Gu C, Cai X, Qu D, Lu L, Xie Y, Jiang S. Griffithsin with a broad-spectrum antiviral activity by binding glycans in viral glycoprotein exhibits strong synergistic effect in combination with a pan-coronavirus fusion inhibitor targeting SARS-CoV-2 spike S2 subunit. Virol Sin 2020; 35: 857-860 DOI: 10.1007/s12250-020-00305-3.

Crossref PubMed Google Scholar
316 OʼKeefe BR, Giomarelli B, Barnard DL, Shenoy SR, Chan PKS, McMahon JB, Palmer KE, Barnett BW, Meyerholz DK, Wohlford-Lenane CL, McCray PB. Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae . J Virol 2010; 84: 2511-2521 DOI: 10.1128/jvi.02322-09.

Crossref PubMed Google Scholar
317 Di Pierro F, Derosa G, Maffioli P, Bertuccioli A, Togni S, Riva A, Allegrini P, Khan A, Khan S, Khan BA, Altaf N, Zahid M, Ujjan ID, Nigar R, Khushk MI, Phulpoto M, Lail A, Devrajani BR, Ahmed S. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med 2021; 14: 2359-2366

Crossref PubMed Google Scholar
318 Rondanelli M, Perna S, Gasparri C, Petrangolini G, Allegrini P, Cavioni A, Faliva MA, Mansueto F, Patelli Z, Peroni G, Tartara A, Riva A. Promising effects of 3-month period of Quercetin Phytosome^® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study. Life 2022; 12: 66 DOI: 10.3390/life12010066.

Crossref PubMed Google Scholar
319 Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, Derosa G, Maffioli P, Togni S, Riva A, Allegrini P, Khan S. Potential clinical benefits of quercetin in the early stage of COVID-19: Results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med 2021; 14: 2807-2816 DOI: 10.2147/IJGM.S318949.

Crossref PubMed Google Scholar
320 McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep 2022; 12: 1-12 DOI: 10.1038/s41598-022-13920-9.

Crossref PubMed Google Scholar

Lizenzen und Reprints

RSS-Feed abonnieren

Teilen / Bookmarken