Subscribe to RSS
DOI: 10.1055/s-0030-1250411
© Georg Thieme Verlag KG Stuttgart · New York
Sleeping Sickness Pathogen (Trypanosoma brucei) and Natural Products: Therapeutic Targets and Screening Systems
Publication History
received June 2, 2010
revised August 31, 2010
accepted Sept. 15, 2010
Publication Date:
13 October 2010 (online)
![](https://www.thieme-connect.de/media/plantamedica/201106/lookinside/thumbnails/10.1055-s-0030-1250411-1.jpg)
Abstract
Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) which is fatal if left untreated. This disease occurs in 36 African countries, south of the Sahara, where 60 million people are at risk of acquiring infection. The current chemotherapy relies on only four drugs, three of which were developed more than 60 years ago. These drugs have many limitations, ranging from oral inabsorption, acute toxicities, short duration of action and the emergence of trypanosomal resistance. Despite decades of use of most of the current trypanocides, little is known about their mode of action. That being said, African trypanosomes continue to be among the most extensively studied parasitic protists to date. Many of their intriguing biological features have been well documented and can be viewed as attractive targets for antitrypanosomal chemotherapy. A considerable number of natural products with diverse molecular structures have revealed antiparasitic potency in the laboratory and represent interesting lead compounds for the development of new and urgently needed antiparasitics. The major validated drug targets in T. brucei are discussed with particular emphasis on those known to be attacked by natural compounds.
Key words
Trypanosoma brucei - Trypanosomatidae - sleeping sickness - natural products - drug targets
References
- 1 World Health Organisation .African trypanosomiasis (sleeping sickness). World Health Organ Fact Sheet, 259, 2006. Available at. http://www.who.int/mediacentre/factsheets/fs259/en/ Accessed May 29, 2010
- 2 World Health Organisation .Control of human African trypanosomiasis: a strategy for the African region. AFRO, June 2005. AFR/RC55/11. Available at. http://www.who.int/trypanosomiasis_african/resources/en/ Accessed May 29, 2010
- 3 Steverding D. The history of African trypanosomiasis. Parasit Vectors. 2008; 1 3
- 4 World Health Organisation .Resolution 50.36, 50th World Health Assembly. Geneva; World Health Organisation 1997
- 5 Centers of Disease Control and Prevention .CDC's Division of Parasitic Diseases: African trypanosomiasis. July 20th 2009. Avilable at. http://www.dpd.cdc.gov/dpdx/HTML/TrypanosomiasisAfrican.htm Accessed May 29, 2010
- 6 Bacchi C J. Chemotherapy of human African trypanosomiasis. Interdiscip Perspect Infect Dis. 2009; 2009 195040
- 7 Steverding D. The development of drugs for treatment of sleeping sickness: a historical review. Parasit Vectors. 2010; 3 15
- 8 Soeiro M N, de Castro S L, de Souza E M, Batista D G, Silva C F, Boykin D W. Diamidine activity against trypanosomes: the state of the art. Curr Mol Pharmacol. 2008; 1 151-161
- 9 Keiser J, Burri C. Physico-chemical properties of the trypanocidal drug melarsoprol. Acta Trop. 2000; 74 101-104
- 10 Oredsson S, Anehus S, Heby O. Inhibition of cell proliferation by DL-a-difluoromethylornithine, a catalytic irreversible inhibitor of ornithine decarboxylase. Acta Chem Scand. 1980; 34 B 457-458
- 11 Yun O, Priotto G, Tong J, Flevaud L, Chappuis F. NECT is next: implementing the new drug combination therapy for Trypanosoma brucei gambiense sleeping sickness. PLoS Negl Trop Dis. 2010; 4 e720
- 12 Wenzler T, Boykin D W, Ismail M A, Hall J E, Tidwell R R, Brun R. New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289. Antimicrob Agents Chemother. 2009; 53 4185-4192
- 13 ClinicalTrials.gov. Human African trypanosomiasis: first in man clinical trial of a new medicinal product, the fexinidazole. Available at. http://www.clinicaltrials.gov/ct2/show/NCT00982904?term=NCT00982904&rank=1 Accessed May 29, 2010
- 14 Bridges D, Gould M, Nerima B, Maser P, Burchmore R J S, De Koning H P. Loss of the high affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Mol Pharmacol. 2007; 71 1098-1108
- 15 Shahi S K, Krauth-Siegel R L, Clayton C E. Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Mol Microbiol. 2002; 43 1129-1138
- 16 Kaminsky R, Maser P. Drug resistance in African trypanosomes. Curr Opin Antiinfect Investig Drugs. 2000; 2 76-82
- 17 McCulloch R. Antigenic variation in African trypanosomes: monitoringprocess. Trends Parasitol. 2004; 20 117-121
- 18 Vreysen M J, Saleh K M, Ali M Y, Abdulla A M, Zhu Z R, Juma K G, Dyck V A, Msangi A R, Mkonyi P A, Feldmann H U. Glossina austeni (Diptera: Glossinidae) eradicated on the island of Unguja, Zanzibar, using the sterile insect technique. J Econ Entomol. 2000; 93 123-135
- 19 Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Aspects Med. 2006; 27 1-93
- 20 Newman D J, Cragg G M. Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007; 70 461-477
- 21 Ioset J R. Natural products for neglected diseases: a review. Curr Org Chem. 2008; 12 643-666
- 22 Enserink M. If artemisinin drugs fail, what's plan B?. Science. 2010; 328 846
- 23 Samuelsson G, Farah M H, Claeson P, Hagos M, Thulin M, Hedberg O, Warfa A M, Hassan A O, Elmi A H, Abdurahman A D, Elmi A S, Abdi Y A, Alin M H. Inventory of plants used in traditional medicine in Somalia. I. Plants of the families Acanthaceae-Chenopodiaceae. J Ethnopharmacol. 1991; 35 25-63
- 24 Freiburghaus F, Kaminsky R, Nkunya M H, Brun R. Evaluation of African medicinal plants for their in vitro trypanocidal activity. J Ethnopharmacol. 1996; 55 1-11
- 25 Freiburghaus F, Jonker S A, Nkunya M H, Mwasumbi L B, Brun R. In vitro trypanocidal activity of some rare Tanzanian medicinal plants. Acta Trop. 1997; 66 79-83
- 26 Hoet S, Opperdoes F, Brun R, Quetin-Leclercq J. Natural products active against African trypanosomes: a step towards new drugs. Nat Prod Rep. 2004; 21 353-364
- 27 Salem M M, Werbovetz K A. Natural products from plants as drug candidates and lead compounds against leishmaniasis and trypanosomiasis. Curr Med Chem. 2006; 13 2571-2598
-
28 Setzer W N, Setzer M C.
Antitrypanosomal agents from higher plants. Williams LAD Biologically active natural products for the 21st century. Kerala; Research Signpost 2006: 47-95 - 29 Gehrig S, Efferth T. Development of drug resistance in Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Treatment of human African trypanosomiasis with natural products (Review). Int J Mol Med. 2008; 22 411-419
- 30 Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov. 2006; 5 941-955
- 31 Berriman M, Ghedin E, Hertz-Fowler C, Blandin G, Renauld H, Bartholomeu D C, Lennard N J, Caler E, Hamlin N E, Haas B, Böhme U, Hannick L, Aslett M A, Shallom J, Marcello L, Hou L, Wickstead B, Alsmark U C, Arrowsmith C, Atkin R J, Barron A J, Bringaud F, Brooks K, Carrington M, Cherevach I, Chillingworth T J, Churcher C, Clark L N, Corton C H, Cronin A, Davies R M, Doggett J, Djikeng A, Feldblyum T, Field M C, Fraser A, Goodhead I, Hance Z, Harper D, Harris B R, Hauser H, Hostetler J, Ivens A, Jagels K, Johnson D, Johnson J, Jones K, Kerhornou A X, Koo H, Larke N, Landfear S, Larkin C, Leech V, Line A, Lord A, Macleod A, Mooney P J, Moule S, Martin D M, Morgan G W, Mungall K, Norbertczak H, Ormond D, Pai G, Peacock C S, Peterson J, Quail M A, Rabbinowitsch E, Rajandream M A, Reitter C, Salzberg S L, Sanders M, Schobel S, Sharp S, Simmonds M, Simpson A J, Tallon L, Turner C M, Tait A, Tivey A R, Van Aken S, Walker D, Wanless D, Wang S, White B, White O, Whitehead S, Woodward J, Wortman J, Adams M D, Embley T M, Gull K, Ullu E, Barry J D, Fairlamb A H, Opperdoes F, Barrell B G, Donelson J E, Hall N, Fraser C M, Melville S E, El-Sayed N M. The genome of the African trypanosome Trypanosoma brucei. Science. 2005; 309 416-422
- 32 Wirtz E, Clayton C. Inducible gene expression in trypanosomes mediated by a prokaryotic repressor. Science. 1995; 268 1179-1183
- 33 Wirtz E, Leal S, Ochatt C, Cross G A. A tightly regulated inducible expression system for conditional gene knock-outs and dominant-negative genetics in Trypanosoma brucei. Mol Biochem Parasitol. 1999; 99 89-101
- 34 Ullu E, Tshudi C, Chakraborty T. RNA interference in protozoan parasites. Cell Microbiol. 2004; 6 509-519
- 35 Frearson J A, Wyatt P G, Gilbert I H, Fairlamb A H. Target assessment for antiparasitic drug discovery. Trends Parasitol. 2007; 23 589-595
- 36 Verlinde C L, Hannaert V, Blonski C, Willson M, Périé J J, Fothergill-Gilmore L A, Opperdoes F R, Gelb M H, Hol W G, Michels P A. Glycolysis as a target for the design of new anti-trypanosome drugs. Drug Resist Updat. 2001; 4 50-65
- 37 Albert M A, Haanstra J R, Hannaert V, Van Roy J, Opperdoes F R, Bakker B M, Michels P A. Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. J Biol Chem. 2005; 280 28306-28315
- 38 Cáceres A J, Michels P A, Hannaert V. Genetic validation of aldolase and glyceraldehyde-3-phosphate dehydrogenase as drug targets in Trypanosoma brucei. Mol Biochem Parasitol. 2010; 169 50-54
- 39 Clarkson Jr A B, Grady R W, Grossman S A, McCallum R J, Brohn F H. Trypanosoma brucei brucei: a systematic screening for alternatives to the salicylhydroxamic acid-glycerol combination. Mol Biochem Parasitol. 1981; 3 271-291
- 40 Nok A J. Azaanthraquinone inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma congolense. Cell Biochem Funct. 2002; 20 205-212
- 41 Minagawa N, Yabu Y, Kita K, Nagai K, Ohta N, Meguro K, Sakajo S, Yoshimoto A. An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei. Mol Biochem Parasitol. 1997; 84 271-280
- 42 Yabu Y, Minagawa N, Kita K, Nagai K, Honma M, Sakajo S, Koide T, Ohta N, Yoshimoto A. Oral and intraperitoneal treatment of Trypanosoma brucei brucei with a combination of ascofuranone and glycerol in mice. Parasitol Int. 1998; 47 131-137
- 43 Yabu Y, Yoshida A, Suzuki T, Nihei C, Kawai K, Minagawa N, Hosokawa T, Nagai K, Kita K, Ohta N. The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice. Parasitol Int. 2003; 52 155-164
- 44 Magae J, Nagai K, Ando K, Tamura G. Differentiation of mouse and human myeloid leukemia cells induced by an antitumor antibiotic, ascofuranone. Agric Biol Chem. 1988; 52 3143-3147
- 45 Drew M E, Morris J C, Wang Z, Wells L, Sanchez M, Landfear S M, Englund P T. The adenosine analog tubercidin inhibits glycolysis in Trypanosoma brucei as revealed by an RNA interference library. J Biol Chem. 2003; 278 46596-46600
- 46 Ngantchou I, Nkwengoua E, Nganso Y, Nyasse B, Denier C, Hannaert V, Schneider B. Antitrypanosomal activity of polycarpol from Piptostigma preussi (Annonaceae). Fitoterapia. 2009; 80 188-191
- 47 Fairlamb A H, Blackburn P, Ulrich P, Chait B T, Cerami A. Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science. 1985; 227 1485-1487
-
48 Krauth-Siegel R L, Comini M A, Schlecker T.
The tryponothione system. Flohé L, Harris JR Peroxiredoxin systems. New York; Springer 2007: 231-251 - 49 Castro H, Tomás A M. Peroxidases of trypanosomatids. Antioxid Redox Signal. 2008; 10 1593-1606
- 50 Willert E K, Phillips M A. Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes. PLoS Pathog. 2008; 4 e1000183
- 51 Comini M A, Guerrero S A, Haile S, Menge U, Lunsdorf H, Flohé L. Validation of Trypanosoma brucei trypanothione synthase as drug target. Free Radic Biol Med. 2004; 36 1289-1302
- 52 Krieger S, Schwarz W, Ariyanayagam M R, Fairlamb A H, Krauth-Siegel R L, Clayton C. Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Mol Microbiol. 2000; 35 542-552
- 53 Wilkinson S R, Horn D, Prathalingam S R, Kelly J M. RNA interfernce identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the African trypanosomes. J Biol Chem. 2003; 278 31640-31646
- 54 Fairlamb A H, Henderson G B, Bacchi C J, Cerami A. In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei. Mol Biochem Parasitol. 1987; 24 185-191
- 55 Kaminsky R, Zweygarth E. Feeder layer-free in vitro assay for screening antitrypanosomal compounds against Trypanosoma brucei brucei and T. b. evansi. Antimicrob Agents Chemother. 1989; 33 881-885
- 56 Zweygarth E, Röttcher D. Efficacy of experimental trypanocidal compounds against a multiple drug-resistant Trypanosoma brucei brucei stock in mice. Parasitol Res. 1989; 75 178-182
- 57 Bacchi C J, Goldberg B, Garofalo-Hannan J, Rattendi D, Lyte P, Yarlett N. Fate of soluble methionine in African trypanosomes: effects of metabolic inhibitors. Biochem J. 1995; 309 737-743
- 58 Koide T, Nose M, Inoue M, Ogihara Y, Yabu Y, Ohta N. Trypanocidal effects of gallic acid and related compounds. Planta Med. 1998; 64 27-30
- 59 Nose M, Koide T, Morikawa K, Inoue M, Ogihara Y, Yabu Y, Ohta N. Formation of reactive oxygen intermediates might be involved in the trypanocidal activity of gallic acid. Biol Pharm Bull. 1998; 21 583-587
- 60 Wang J C. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002; 3 430-440
- 61 Liu B, Liu Y, Motyka S A, Agbo E E, Englund P T. Fellowship of the rings: the replication of kinetoplast DNA. Trends Parasitol. 2005; 21 363-369
- 62 Scocca J R, Shapiro T A. A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes. Mol Microbiol. 2008; 67 820-829
- 63 Bakshi R P, Shapiro T A. RNA interference of Trypanosoma brucei topoisomerase IB: both subunits are essential. Mol Biochem Parasitol. 2004; 136 249-255
- 64 Kulikowicz T, Shapiro T A. Distinct genes encode type II topoisomerases for the nucleus and mitochondrion in the protozoan parasite Trypanosoma brucei. J Biol Chem. 2006; 281 3048-3056
- 65 Wang Z, Englund P T. RNA interference of a trypanosome topoisomerase II causes progressive loss of mitochondrial DNA. EMBO J. 2001; 20 4674-4683
- 66 Topcu Z. DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther. 2001; 269 405-416
- 67 Bodley A L, Shapiro T A. Molecular and cytotoxic effects of camptothecin,a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proc Natl Acad Sci USA. 1995; 92 3726-3730
- 68 Worthen C, Jensen B C, Parsons M. Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma brucei. PLoS Negl Trop Dis. 2010; 4 e678
- 69 Yardley V, Snowdon D, Croft S L, Hazra B. In vitro activity of diospyrin and its derivatives against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei brucei. Phytother Res. 1996; 10 559-562
- 70 Hoet S, Opperdoes F, Brun R, Adjakidjé V, Quetin-Leclercq J. In vitro antitrypanosomal activity of ethnopharmacologically selected Beninese plants. J. Ethnopharmacol. 2004; 91 37-42
- 71 Deterding A, Dungey F A, Thompson K A, Steverding D. Anti-trypanosomal activities of DNA topoisomerase inhibitors. Acta Trop. 2005; 93 311-316
- 72 Merschjohann K, Sporer F, Sterverding, Wink M. In vitro effect of alkaloids on bloodstream forms of Trypanosoma brucei and T. congolense. Planta Med. 2001; 67 623-627
- 73 Mazzini S, Bellucci M C, Mondelli R. Mode of binding of the cytotoxic alkaloid berberine with the double helix oligonucleotides D(AAGAATTCTT)2. Biorg Med Chem. 2003; 11 505-514
- 74 Stiborova M, Simanek V, Frei E, Hobza P, Ulrichova J. DNA adduct formation from quaternary benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine as revealed by the 32P-postlabeling technique. Chem Biol Interact. 2002; 140 1096-1101
- 75 Zhang F L, Casey P J. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996; 65 241-269
- 76 Eastman R T, Buckner F S, Yokoyama K, Gelb M H, Van Voorhis W C. Fighting parasitic disease by blocking protein farnesylation. J Lipid Res. 2006; 47 233-240
- 77 Ali B R, Pal A, Croft S L, Taylor R J, Field M C. The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria. Mol Biochem Parasitol. 1999; 104 67-80
- 78 Zhou J, Giannakakou P. Targeting microtubules for cancer chemotherapy. Curr Med Chem Anticancer Agents. 2005; 5 65-71
- 79 Morgan R E, Werbovetz K A. Selective lead compounds against kinetoplastid tubulin. Adv Exp Med Biol. 2008; 625 33-47
- 80 Ochola D O, Prichard R K, Lubega G W. Classical ligands bind tubulin of trypanosomes and inhibit their growth in vitro. J Parasitol. 2002; 88 600-604
- 81 Frearson J A, Brand S, McElroy S P, Cleghorn L A, Smid O, Stojanovski L, Price H P, Guther M L, Torrie L S, Robinson D A, Hallyburton I, Mpamhanga C P, Brannigan J A, Wilkinson A J, Hodgkinson M, Hui R, Qiu W, Raimi O G, van Aalten D M, Brenk R, Gilbert I H, Read K D, Fairlamb A H, Ferguson M A, Smith D F, Wyatt P G. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature. 2010; 464 728-732
- 82 el Kouni M H. Potential chemotherapeutic targets in the purine metabolism of parasites. Pharmacol Ther. 2003; 99 283-309
- 83 Lee S H, Stephens J L, Englund P T. A fatty-acid synthesis mechanism specialized for parasitism. Nat Rev Microbiol. 2007; 5 287-297
- 84 Naula C, Parsons M, Mottram J C. Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta. 2005; 1754 151-159
- 85 Agüero F, Al-Lazikani B, Aslett M, Berriman M, Buckner F S, Campbell R K, Carmona S, Carruthers I M, Chan A W, Chen F, Crowther G J, Doyle M A, Hertz-Fowler C, Hopkins A L, McAllister G, Nwaka S, Overington J P, Pain A, Paolini G V, Pieper U, Ralph S A, Riechers A, Roos D S, Sali A, Shanmugam D, Suzuki T, Van Voorhis W C, Verlinde C L. Genomic-scale prioritization of drug targets: the TDR Targets database. Nat Rev Drug Discov. 2008; 7 900-907
- 86 Kubata B K, Nagamune K, Murakami N, Merkel P, Kabututu Z, Martin S K, Kalulu T M, Huq M, Yoshida M, Ohnishi-Kameyama M, Kinoshita T, Duszenko M, Urade Y. Kola acuminata proanthocyanidins: a class of anti-trypanosomal compounds effective against Trypanosoma brucei. Int J Parasitol. 2005; 35 91-103
- 87 Adamson R H, Zaharevitz D W, Johns D G. Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2′-deoxycoformycin. Pharmacology. 1977; 15 84-89
- 88 Vodnala S K, Ferella M, Lundén-Miguel H, Betha E, van Reet N, Amin D N, Oberg B, Andersson B, Kristensson K, Wigzell H, Rottenberg M E. Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin. PLoS Negl Trop Dis. 2009; 3 e495
- 89 Mamani-Matsuda M, Rambert J, Malvy D, Lejoly-Boisseau H, Daulouède S, Thiolat D, Coves S, Courtois P, Vincendeau P, Mossalayi M D. Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages. Antimicrob Agents Chemother. 2004; 48 924-929
- 90 Kuettel S, Mosimann M, Mäser P, Kaiser M, Brun R, Scapozza L, Perozzo R. Adenosine inase of T. b. rhodesiense identified as the putative target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine using chemical proteomics. PLoS Negl Trop Dis. 2009; 3 e506
- 91 Denise H, Giroud C, Barrett M P, Baltz T. Affinity chromatography using trypanocidal arsenical drugs identifies a specific interaction between glycerol-3-phosphate dehydrogenase from Trypanosoma brucei and Cymelarsan. Eur J Biochem. 1999; 259 339-346
Dr. Véronique Hannaert
Research Unit for Tropical Diseases
de Duve Institute and Laboratory of Biochemistry
Université catholique de Louvain
Avenue Hippocrate 74
1200 Brussels
Belgium
Phone: +32 27 64 74 72
Fax: +32 27 62 68 53
Email: veronique.hannaert@uclouvain.be