Undeveloped Region in Target-Strategies and Potential in Antiviral Drug Discovery

Abstract

Drug resistance is a looming threat to global health security, undermining the effectiveness of current treatments and increasing treatment failures. To address this challenge, it is necessary to explore innovative strategies by identifying new binding mechanisms and targeting previously undeveloped therapeutic avenues. This paper reviewed the potential of leveraging undeveloped domains to combat drug resistance and proposes a range of methodologies to accurately identify those specific targets. There is also an extensive review of the challenges associated with targeting undeveloped areas and strategies to effectively address them. In this process, the application of artificial intelligence (AI) can effectively improve the efficiency of drug design, while appropriate attention should be paid to the physicochemical and drug-like properties of pharmaceutical compounds in the realm of drug discovery. Given the above, focusing on these undeveloped areas could provide a promising pathway to address drug resistance; however, achieving this objective necessitates sustained investigative efforts and inventive approaches.

Keywords

drug resistance - targeting undeveloped sites - antiviral drug design - target-based drug discovery

Introduction

Antiviral medications exert their therapeutic impact by precisely targeting different phases of the viral replication cycle, effectively curbing the capacity of viruses to infect host cells and proliferate. The mechanisms encompass a multifaceted approach: (a) preventing viral entry into cells; (b) disrupting viral replication by incorporating viral nucleic acids; (c) inhibiting viral enzyme activity; and (d) impeding the release of newly formed viral particles from host cells. Despite the effectiveness of these drugs, the emergence of drug resistance poses a significant concern, thereby it is crucial to explore novel antiviral therapies as well as strategic utilization of existing treatments. The phenomenon is frequently associated with mutations in target proteins that prevent the binding of the drug.[1] However, since the viral population is a mosaic of diverse genotypes, the diversity may emerge from elevated mutation rates during replication,[2] [3] the selection process for drug-resistant viruses can be rapid.

Current strategies to combat antiviral drug resistance focus on improving the efficacy and selectivity. These approaches include the modification of mechanisms of action, for example, exploring covalent drugs and proteolysis-targeting chimeras, and targeting allosteric sites.[4] However, in strategies aimed at enhancing efficacy, the development of drugs that target previously undeveloped sites may be a promising avenue to offer innovative therapeutic options capable of effectively addressing existing resistance issues.

Targeting undeveloped sites allows more specific drugs to be designed that minimize interference with normal cellular or physiological processes, thereby reducing toxic side effects. These undeveloped sites may exhibit lower mutation rates or play a critical role in the viral life cycle, making drugs that target them less likely to induce resistance.[5] [6] For example, nirmatrelvir and ensitrelvir both target the same binding site; however, their distinct binding modes result in minimal cross-resistance between them.[7] The development of first-in-class drugs that target previously undeveloped sites[8] could provide pharmaceutical researchers with a competitive advantage in the marketplace, as well as potentially substantial economic benefits. In this review, we will focus on chemotype-specific resistance to chemical inhibitors, as these mechanisms are increasingly being elucidated. We will highlight recent examples of drug-resistance analyses and innovative chemical strategies developed to effectively combat this resistance ([Fig. 1]).

Fig. 1 Strategies aimed at targeting previously undeveloped regions to overcome resistance to targeted molecular therapeutics.

Inhibitors with Novel Binding Modes

Even within the confines of a single binding site, the mode of binding can be substantially different. This insight opens up a promising avenue for identifying compounds with novel mechanisms of action. M2 proton channel blockers of the influenza A virus (A/M2) are a category of antiviral agents, of which amantadine ([Fig. 2], compound 1) and rimantadine are notable examples that have been approved by the U.S. Food and Drug Administration (FDA).[9] The advent of high-resolution A/M2 structures has strengthened their role in rational drug design,[10] with three primary resistance mutations identified in A/M2 being V27A, L26F, and S31N.[11] [12]

Fig. 2 Binding modes of compounds 1 (green) and 2 (pink) (PDB code: 2LY0).[14]

Molecular dynamics (MD) simulations have forecasted a pore radius of less than 1.4 Å for the Asn31 site, whereas, an expanded pore radius of 2.6 Å for the Ser31 position.[13] Compound 1 has high mobility within the N31 channel, hindering its binding efficacy. Thus, compound 2 ([Fig. 2]) was synthesized to block the channel blockade and exhibited enhanced antiviral efficacy against the S31N mutant compared to compound 1's activity against the wild-type (WT) M2, highlighting the potential of the compound for further development.[14] Compound 2 is securely anchored within the central cavity of the S31N mutant ([Fig. 2]). Within the Asn31–Gly34 region, spatial accommodation of the adamantane scaffold is restricted, whereas, the thiophene moiety of compound 2 was involved in favorable hydrophobic interactions. Compound 2 exhibits stronger inhibitory activity against the S31N mutant, which may be attributed to the increased flexibility of the compound to adopt various binding conformations within the interaction site as compared to compound 1.

The antiviral agent PF-00835231 is a rupintrivir derivative that specifically targets the main protease (M^pro) of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and has been subjected to further optimization to enhance its oral bioavailability. This led to the development of nirmatrelvir ([Fig. 3], compound 3). Ensitrelvir (4) was discovered through a combination of virtual screening and subsequent biological evaluation of a compound library, followed by optimization using a structure-based drug design approach.[15] The mutant ∆P168/A173V exhibits a significant 47.8-fold increase in resistance to compound 3 compared to the virus. However, a relatively mild 3.9-fold increase in resistance to compound 4.

Fig. 3 Binding modes of compounds 3 (magenta) and 4 (green) at the active site of SARS-CoV-2 M^pro (PDB codes: 7VU6, 7SI9).[42] [43] The symbol ΔP168 demonstrated a single-residue deletion at position Pro168.

The observed disparities can be attributed to the distinct binding modes of the compounds ([Fig. 3]). Compound 3 has a V-shaped conformation within the binding pocket, while compound 4 has a T-shaped structure. Compound 3 forms covalent bonds with the active site of M^pro, whereas compound 4 interacts with M^pro through non-covalent interactions. These findings emphasize the potential for the development of alternative protease inhibitors that exhibit different modes of action and drug resistance profiles. The identification of these molecular mechanisms contributes to the development of future inhibitors, particularly compound 4, which requires a precise understanding of its molecular inhibition mechanism due to its characterization as the first non-covalent, non-peptide oral inhibitor.

Exploiting Novel Binding Cavity Spaces

It is a viable strategy to develop pharmaceuticals based on three-dimensional structural information of target proteins. By understanding the interactions between the drug and its target, along with identifying previously unexplored binding sites, drug molecules can be specifically designed to effectively occupy these binding sites. The advantage of this approach is its capacity to accurately target distinct binding sites, thereby enhancing both the specificity and potency of the drug.

A prevalent strategy in the design of HIV-1 reverse transcriptase inhibitors (RTIs) involves the synthesis of compounds that simultaneously occupy multiple binding sites.[16] [17] [18] In current antiretroviral therapy options, there is an urgent need for novel RTIs that provide enhanced resistance profiles and improved safety. By targeting the tolerant region II ([Fig. 4]), a series of innovative derivatives were identified. Compound 6 exhibits broad-spectrum antiviral activity and higher resistance against RTI-resistant variants compared to compound 5. Notably, it also inhibits cytochrome P450 enzyme's activity compared to compound 5 with a decreased likelihood of hERG blockade.[19]

Fig. 4 Co-crystal structure of etravirine (5), compound 6, and HIV-1 RT complex (PDB code: 3MEC).[44]

In the quest for novel HIV protease inhibitors, a strategy emphasizing the expansion of the ligand-binding pocket has been employed ([Fig. 5]).[20] [21] For instance, the potency of darunavir (7), which features P1 phosphonate modifications (8), can be augmented against resistant variants by expanding the size of P1′ hydrophobic groups and incorporating diverse P2′ fragments.

Fig. 5 Darunavir (7), and the binding mode of the corresponding P1 phosphonate analog GS-8374 (PDB code: 2I4W)[21] with compound 8.

The discovery of neuraminidase (NA) inhibitors that target the 150-cavity illustrates a similar drug design approach ([Fig. 6]). NAs are crucial glycoproteins located on the surface antigens,[22] and promising candidates for the development of anti-influenza virus therapeutics.[23] Among the approved NA inhibitors, oseltamivir, and zanamivir have been utilized worldwide since the influenza season of 1999 to 2000.[24] [25]

Fig. 6 Oseltamivir carboxylate (9), and docking results of compound 10 (cyan) with NA (PDB code: 2HU0).[26]

NAs can be divided into two distinct groups, reflecting their phylogenetic relationships.[26] The 150-loop of group-1 displays an open conformation, with a 150-cavity in its active site, which suggests new opportunities for inhibitor design.[26] By incorporating substituents that specifically target the 150-cavity into existing NA inhibitors, novel drugs may be developed.[26] [27]

The 150-cavity has been the focus in the design of oseltamivir carboxylate ([Fig. 6], compound 9) and its derivatives, of which compound 10 is a potent and selective inhibitor of group-1 NA. Compound 10 showed the highest inhibitory activity against NAs ([Fig. 6]).[28] In addition, the H274Y enzyme showed sensitivity to compound 10 (IC₅₀ = 0.16 μmol/L). Although the H274Y mutation is known to confer resistance to oseltamivir, compound 10 exhibits an impressive 12-fold increase in inhibitory activity against oseltamivir-resistant virus.

Optimal binding of compound 10 within the NA (N1 subtype) was ascertained through molecular docking according to a reported study.[28] As shown in [Fig. 6], the active site and the 150-cavity were occupied by compound 10. Subsequent optimization in this region led to the development of compounds with exceptional activity.[29] [30]

SARS-CoV-2 is thought to cause respiratory infections that can be fatal in severe cases. During the COVID-19 pandemic, the rise of various mutated strains has spurred scientific efforts to explore innovative treatment options to combat drug resistance to these variants. Currently, the FDA has authorized two categories of antiviral medications: M^pro inhibitors and RNA-dependent RNA polymerase inhibitors; however, resistance to both classes has been observed. In addition to these targets, papain-like protease (PL^pro) inhibitors come to clinical research studies. Other targets identified for COVID-19 include spike and nucleocapsid proteins. These research advancements offer novel perspectives and potential targets for the clinical management of COVID-19, facilitating the development of effective therapeutic strategies.

The PL^pro has emerged as a promising target in the pursuit of new mechanisms for antiviral therapy. Based on inhibitors 11 and 12 ([Fig. 7]), a novel covalent PL^pro inhibitor (13) has been successfully designed. Co-crystal structure analysis revealed that compound 13 occupies the ubiquitin Val70 (Val70^Ub) pocket. Leveraging this insight, the structure of compound 13 was optimized, leading to the development of compound 14, whose configuration effectively targets both the BL2 groove and Val70^Ub ([Fig. 7]), showing inhibitory activity against resistant viral strains.[31]

Fig. 7 Atomic model of the binding site of compound 14 (cyan) and compound 13 (pink) in SARS-CoV-2 PL^pro (PDB code: 8UOB, 8UVM).[31]

According to the detailed structure of PL^pro, the addition of oxadiazole and aryl carboxylic acid groups to compound 15 could significantly enhance the enzymatic inhibitory activity of the compound. As a result, a series of 1,2,4-oxadiazole derivatives were designed and synthesized. Among them, compound 16 ([Fig. 8]) demonstrated remarkable PL^pro inhibitory activity (IC₅₀ = 1.0 μmol/L) and antiviral efficacy (EC₅₀ = 4.3 μmol/L), and also showed moderate oral bioavailability.[32]

Fig. 8 Design strategy of compound 16 based on compound 15. Compound 15 is presented as a stick model (orange) (PDB code: 7CMD).[45]

The M^pro of SARS-CoV-2 is a promising target for the discovery of antiviral drugs. Most research has focused on the S4-S1 pocket; however, whether the S1′-S3′ pocket could be an innovative site for drug development remains unexplored. Notably, phenylalanine or tryptophan residues preferentially appeared at position S3′, while alanine preferentially appeared at position S1′ ([Fig. 9]). Liu et al suggested that peptide 17 (VKLQAIFR) showed a strong binding affinity with the S1′-S3′ pocket,[33] with a K _d value of 3.89 μmol/L and was therefore selected as the template for further peptide design. Utilizing a warhead, a peptidomimetic inhibitor, designated as compound 18, was created. This compound has an antiviral EC₅₀ value of 0.49 μmol/L and acts as an immune protector by inhibiting the antagonistic effect of the host NF-κB innate immune responses induced by SARS-CoV-2 M^pro.[33]

Fig. 9 Co-crystal structure of peptide 17 (yellow) and the SARS-CoV-2 M^pro (PDB code: 8GWS).[33]

This design strategy is frequently employed in the development of small molecules. Based on a preclinical candidate small-molecule inhibitor ([Fig. 10], compound 19) and utilizing click chemistry for rapid discovery of potent inhibitors targeting the S2 pocket of the M^pro of SARS-CoV-2, a series of novel 1,2,3-triazole derivatives have been identified as potent inhibitors of M^pro with significant anti-SARS-CoV-2 activity. Among them, compound 20 ([Fig. 10]) demonstrates superior potency compared to nirmatrelvir (EC₅₀ = 1.95 μmol/L) and similar efficacy to ensitrelvir (EC₅₀ = 0.11 μmol/L). Notably, compound 20 shows robust antiviral activity against several SARS-CoV-2 variants, including Gamma, Delta, and Omicron (EC₅₀ = 0.13–0.26 μmol/L), as well as HCoV-OC43, highlighting its broad-spectrum antiviral potential. Notably, compound 20 still retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M^pro (EC₅₀ = 0.26 and 0.15 μmol/L, respectively).[34]

Fig. 10 Co-crystal structure of compounds 19 (cyan), 20 (pink), and the SARS-CoV-2 M^pro (PDB code: 9G01).[34]

Conclusion

Drug resistance poses a significant challenge to global public health, compromising the efficacy of existing treatments and resulting in treatment failures. This paper outlines strategies targeting undeveloped sites to combat the growing prevalence of drug resistance, including the identification of new binding modes and the focus on novel binding sites. These strategies have been extensively applied in the domain of antiviral research specifically concerning influenza A, SARS-CoV-2, and HIV-1.

While targeting undeveloped sites presents a promising strategy, it comes with certain challenges. An essential aspect is the identification of undeveloped sites. To identify these hidden allosteric sites, researchers have developed a variety of computational and experimental methods. For instance, MD simulations can sample multiple conformations of proteins, thereby revealing unexplored allosteric sites.[35] MD simulations are suitable for investigating the dynamic properties of proteins, such as conformational changes and allosteric effects. Markov state models can provide an atomic-level detailed view of biomolecules and help identify hidden allosteric sites. In the realm of experimental techniques, cysteine trapping, and room-temperature X-ray crystallography significantly advance the study of protein dynamics and allosteric mechanisms. These advancements facilitate the identification of undeveloped allosteric sites in large protein systems.[36] Moreover, the integration of artificial intelligence (AI) and machine learning technologies is gaining significant traction in drug design. The ability of AI to adeptly process and interpret vast bioinformatics data to reveal underlying patterns and correlations has improved the precision of potential drug target identification and accelerated the drug screening and design processes.[37] AI-driven target discovery technologies of in silico medicine have been extensively applied in various fields. For example, PandaOmics™, an AI biological target discovery platform, has successfully identified several previously unreported potential therapeutic targets for amyotrophic lateral sclerosis.[38] These technologies will facilitate the research and development of antiviral drugs targeting undeveloped sites.

The strategy of targeting new sites is often associated with an increased molecular weight after structural optimization, which subsequently alters the physicochemical properties and drug-likeness. Therefore, it is essential to conduct multidimensional drug-likeness optimization of lead compounds under the guidance of structural biology information. This approach should incorporate novel drug-likeness parameters for early virtual prediction or actual assessment of lead compounds. For instance, parameters such as ligand efficiency, lipophilic efficiency, and Fsp3 can be utilized.[39] [40] [41]

In summary, the study of previously undeveloped sites offers fresh insights and opportunities to combat drug resistance for antiviral strategies, underscoring their potential to play a role in the future management of viral infections, driven by ongoing advancements in biotechnology, and our evolving comprehension of biological processes.

Conflict of Interest

None declared.

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Publication History

Received: 29 September 2024

Accepted: 23 January 2025

Article published online:
24 February 2025