Drug development against sleeping sickness: Old wine in new bottles?

Current Medicinal Chemistry

Volumn 21, Issue 15, 2014, Pages 1713-1727

  Stein, J ^a   Mogk, S ^a   Mudogo, C N ^a   Sommer, B P ^a   Scholze, M ^a   Meiwes, A ^a   Huber, M ^a   Gray, A ^a   Duszenko, M ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Apoptosis; Autophagy; Drug development; Human african trypanosomiasis; Sleeping sickness; Trypanosoma brucei

Indexed keywords

ARSANILIC ACID; ARSPHENAMINE; EFLORNITHINE; MELARSOPROL; NATURAL PRODUCT; NIFURTIMOX; PROTEINASE; SURAMIN; TRYPANOTHIONE; TRYPARSAMIDE; ANTITRYPANOSOMAL AGENT;

AFRICAN TRYPANOSOMIASIS; ANEMIA; APOPTOSIS; ARTICLE; AUTOPHAGY; BLINDNESS; BLOOD CLOTTING DISORDER; BRAIN DISEASE; CELL DENSITY; CELL DIFFERENTIATION; CENTRAL NERVOUS SYSTEM INFECTION; DIARRHEA; DRUG FATALITY; DRUG POTENCY; DRUG TARGETING; ENERGY METABOLISM; FATIGUE; FEVER; GASTROINTESTINAL SYMPTOM; HEADACHE; HEARING IMPAIRMENT; HEART FAILURE; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPERTRANSAMINASEMIA; HYPOCALCEMIA; KIDNEY FAILURE; LIFE CYCLE STAGE; NEUROPATHY; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; OXIDATION REDUCTION REACTION; PARALYSIS; PERIPHERAL NEUROPATHY; POLYNEUROPATHY; PRURITUS; RASH; SKIN NECROSIS; THROMBOCYTOPENIA; TREMOR; VOMITING; X RAY CRYSTALLOGRAPHY; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECTS; GROWTH, DEVELOPMENT AND AGING; TRYPANOSOMA; TRYPANOSOMIASIS, AFRICAN;

ANIMALS; DRUG DISCOVERY; ENERGY METABOLISM; HUMANS; LIFE CYCLE STAGES; TRYPANOCIDAL AGENTS; TRYPANOSOMA; TRYPANOSOMIASIS, AFRICAN;

EID: 84899793756     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867320666131119121636     Document Type: Article

References (109)

1. Pays, E.; Vanhollebeke, B. Mutual self-defence: the trypanolytic factor story. Microbes Infect., 2008, 10(9), 985-989.
2. http://www.who.int/mediacentre/factsheets/fs259/en/ July 2013.
3. LaCount, D.J.; Gruszynski, A.E.; Grandgenett, P.M.; Bangs, J.D.; Donelson, J.E. Expression and function of the Trypanosoma brucei major surface protease (GP63) genes. J. Biol. Chem., 2003, 278(27), 24658-24664.
4. Roditi, I.; Schwarz, H.; Pearson, T.W.; Beecroft, R.P.; Liu, M.K.; Richardson, J.P.; Buhring, H.J.; Pleiss, J.; Bulow, R.; Williams, R.O.; et al. Procyclin gene expression and loss of the variant surface glycoprotein during differentiation of Trypanosoma brucei. J. Cell Biol., 1989, 108(2), 737-746.
5. Vickerman, K.; Tetley, L.; Hendry, K.A.; Turner, C.M. Biology of African trypanosomes in the tsetse fly. Biol. Cell., 1988, 64(2), 109-119.
6. Overath, P.; Chaudhri, M.; Steverding, D.; Ziegelbauer, K. Invariant surface proteins in bloodstream forms of Trypanosoma brucei. Parasitol. Today, 1994, 10(2), 53-58.
7. Barry, J.D.; Turner, C.M. The dynamics of antigenic variation and growth of African trypanosomes. Parasitol. Today, 1991, 7(8), 207-211.
8. Turner, C.M. The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei. FEMS Microbiol. Lett., 1997, 153(1), 227-231.
9. Marcello, L.; Barry, J.D. Analysis of the VSG gene silent archive in Trypanosoma brucei reveals that mosaic gene expression is prominent in antigenic variation and is favored by archive substructure. Genome Res., 2007, 17(9), 1344-1352.
10. Pays, E.; Guyaux, M.; Aerts, D.; Van Meirvenne, N.; Steinert, M. Telomeric reciprocal recombination as a possible mechanism for antigenic variation in trypanosomes. Nature, 1985, 316(6028), 562-564.
11. Barbet, A.F.; Kamper, S.M. The importance of mosaic genes to trypanosome survival. Parasitol. Today, 1993, 9(2), 63-66.
12. Capewell, P.; Monk, S.; Ivens, A.; Macgregor, P.; Fenn, K.; Walrad, P.; Bringaud, F.; Smith, T.K.; Matthews, K.R. Regulation of Total and Polysomal mRNA during Development within Its Mammalian Host. PloS one, 2013, 8(6), e67069.
13. Vassella, E.; Reuner, B.; Yutzy, B.; Boshart, M. Differentiation of African trypanosomes is controlled by a density sensing mechanism which signals cell cycle arrest via the cAMP pathway. J. Cell Sci., 1997, 110( Pt 21), 2661-2671.
14. Fenn, K.; Matthews, K.R. The cell biology of Trypanosoma brucei differentiation. Curr. Opin. Microbiol., 2007, 10(6), 539-546.
15. Figarella, K.; Rawer, M.; Uzcategui, N.L.; Kubata, B.K.; Lauber, K.; Madeo, F.; Wesselborg, S.; Duszenko, M. Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form. Cell Death Differ., 2005, 12(4), 335-346.
16. Mulenga, C.; Mhlanga, J.D.; Kristensson, K.; Robertson, B. Trypanosoma brucei brucei crosses the blood-brain barrier while tight junction proteins are preserved in a rat chronic disease model. Neuropathol. Appl. Neurobiol., 2001, 27(1), 77-85.
17. Grab, D.J.; Kennedy, P.G. Traversal of human and animal trypanosomes across the blood-brain barrier. J. Neurovirol., 2008, 14(5), 344-351.
18. Wolburg, H.; Mogk, S.; Acker, S.; Frey, C.; Meinert, M.; Schonfeld, C.; Lazarus, M.; Urade, Y.; Kubata, B.K.; Duszenko, M. Late stage infection in sleeping sickness. PloS one, 2012, 7(3), e34304.
19. Wilkinson, S.R.; Kelly, J.M. Trypanocidal drugs: mechanisms, resistance and new targets. Expert Rev. Mol. Med., 2009, 11, e31.
20. Schlitzer, M. Wirkstoffezur Behandlung der Afrikanischen Schlafkrankheit. Pharmazie in unserer Zeit, 2009, 38(6), 552-558.
21. Jennings, F.W.; Whitelaw, D.D.; Holmes, P.H.; Chizyuka, H.G.; Urquhart, G.M. The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy. Int. J. Parasitol., 1979, 9(4), 381-384.
22. Lambrecht, F. Trypanosomes and hominid evolution. Bioscience, 1985, 35, 640-646.
23. Hamm, B.; Schindler, A.; Mecke, D.; Duszenko, M. Differentiation of Trypanosoma brucei bloodstream trypomastigotes from long slender to short stumpy-like forms in axenic culture. Mol. Biochem. Parasitol., 1990, 40(1), 13-22.
24. Kubata, B.K.; Duszenko, M.; Martin, K.S.; Urade, Y. Molecular basis for prostaglandin production in hosts and parasites. Trends Parasitol., 2007, 23(7), 325-331.
25. Hayaishi, O.; Urade, Y. Prostaglandin D2 in sleep-wake regulation: recent progress and perspectives. Neuroscientist, 2002, 8(1), 12-15.
26. Onoe, H.; Ueno, R.; Fujita, I.; Nishino, H.; Oomura, Y.; Hayaishi, O. Prostaglandin D2, a cerebral sleep-inducing substance in monkeys. Proc. Natl. Acad. Sci. USA, 1988, 85(11), 4082-4086.
27. Pentreath, V.W.; Rees, K.; Owolabi, O.A.; Philip, K.A.; Doua, F. The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Trans. R. Soc. Trop. Med. Hyg., 1990, 84(6), 795-799.
28. Steverding, D. The history of African trypanosomiasis. Parasites & vectors, 2008, 1(1), 3.
29. Boyce, R. The Treatment of Sleeping Sickness and Other Trypanosomiases by the Atoxyl and Mercury Method. Brit. Med. J., 1907, 2(2437), 624-625.
30. Goldmann, E. Vitalfärbung am Zentralnervensystem. Abh. Preuss. Akd. Wiss. Phys., 1913, 1-13.
31. Fourneau, E.; Tréfouël, J.; Tréfouël, T.; Vallée, J. Sur une nouvelle série de médicaments trypanocides. C. R. Séances Acad. Sci. , 1924, 178, 675.
32. Jacobs, R.T.; Nare, B.; Phillips, M.A. State of the art in African trypanosome drug discovery. Curr. Top. Med. Chem., 2011, 11(10), 1255-1274.
33. Friedheim, E.A. Mel B in the treatment of human trypanosomiasis. Am. J. Trop. Med. Hyg., 1949, 29(2), 173-180.
34. Barrett, M.P.; Boykin, D.W.; Brun, R.; Tidwell, R.R. Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br. J. Pharmacol., 2007, 152(8), 1155-1171.
35. Balasegaram, M.; Harris, S.; Checchi, F.; Ghorashian, S.; Hamel, C.; Karunakara, U. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull. W.H.O, 2006, 84(10), 783-791.
36. Bacchi, C.J.; Nathan, H.C.; Hutner, S.H.; McCann, P.P.; Sjoerdsma, A. Polyamine metabolism: a potential therapeutic target in trypanosomes. Science, 1980, 210(4467), 332-334.
37. Milord, F.; Pepin, J.; Loko, L.; Ethier, L.; Mpia, B. Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness. Lancet, 1992, 340(8820), 652-655.
38. Priotto, G.; Kasparian, S.; Ngouama, D.; Ghorashian, S.; Arnold, U.; Ghabri, S.; Karunakara, U. Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Congo. Clin. Infect. Dis., 2007, 45(11), 1435-1442.
39. Kaiser, M.; Bray, M.A.; Cal, M.; Bourdin Trunz, B.; Torreele, E.; Brun, R. Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob. Agents Chemother., 2011, 55(12), 5602-5608.
40. Opperdoes, F.R.; Borst, P. Localization of nine glycolytic enzymes in a microbody- like organelle in Trypanosoma brucei: the glycosome. FEBS Lett., 1977, 80(2), 360-364.
41. Parsons, M. Glycosomes: parasites and the divergence of peroxisomal purpose. Mol. Microbiol., 2004, 53(3), 717-724.
42. Nihei, C.; Fukai, Y.; Kita, K. Trypanosome alternative oxidase as a target of chemotherapy. Biochim. Biophys. Acta, 2002, 1587(2-3), 234-239.
43. Grady, R.W.; Bienen, E.J.; Dieck, H.A.; Saric, M.; Clarkson, A.B., Jr. N-n-alkyl-3,4- dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo. Antimicrob. Agents Chemother., 1993, 37(5), 1082-1085.
44. Opperdoes, F.R.; Aarsen, P.N.; van der Meer, C.; Borst, P. Trypanosoma brucei: an evaluation of salicylhydroxamic acid as a trypanocidal drug. Exp. Parasitol., 1976, 40(2), 198-205.
45. 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(2), 271-280.
46. Saimoto, H.; Kido, Y.; Haga, Y.; Sakamoto, K.; Kita, K. Pharmacophore identification of ascofuranone, potent inhibitor of cyanideinsensitive alternative oxidase of Trypanosoma brucei. J. Biochem., 2013, 153(3), 267-273.
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(4693), 1485-1487.
48. Comini, M.A.; Krauth-Siegel, R.L.; Flohe, L. Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes. Biochem. J., 2007, 402(1), 43-49.
49. Comini, M.A.; Flohe, L. Trypanosomatid Diseases: Trypanothione- Based Redox Metabolism of Trypanosomatids. Wiley-Blackwell, 2013, ISBN: 978-3-527-33255-7
50. Ferguson, M.A.; Low, M.G.; Cross, G.A. Glycosyl-sn-1,2- dimyristylphosphatidylinositol is covalently linked to Trypanosoma brucei variant surface glycoprotein. J. Biol. Chem., 1985, 260(27), 14547-14555.
51. Ferguson, M.A.; Brimacombe, J.S.; Brown, J.R.; Crossman, A.; Dix, A.; Field, R.A.; Guther, M.L.; Milne, K.G.; Sharma, D.K.; Smith, T.K. The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness. Biochim. Biophys. Acta, 1999, 1455(2-3), 327-340.
52. 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(7289), 728-732.
53. McKerrow, J.H.; Rosenthal, P.J.; Swenerton, R.; Doyle, P. Development of protease inhibitors for protozoan infections. Curr. Opin. Infect. Dis., 2008, 21(6), 668-672.
54. Rascon, A.A., Jr.; McKerrow, J.H. Synthetic and Natural Protease Inhibitors Provide Insights into Parasite Development, Virulence, and Pathogenesis. Curr. Med. Chem., 2013, 20(25), 3078-3102.
55. Mackey, Z.B.; O'Brien, T.C.; Greenbaum, D.C.; Blank, R.B.; McKerrow, J.H. A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. J. Biol. Chem., 2004, 279(46), 48426-48433.
56. Steverding, D.; Sexton, D.W.; Wang, X.; Gehrke, S.S.; Wagner, G.K.; Caffrey, C.R. Trypanosoma brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int. J. Parasitol., 2012, 42(5), 481-488.
57. Scory, S.; Caffrey, C.R.; Stierhof, Y.D.; Ruppel, A.; Steverding, D. Trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor Z-phe-ala- CHN2. Exp. Parasitol., 1999, 91(4), 327-333.
58. Abdulla, M.H.; O'Brien, T.; Mackey, Z.B.; Sajid, M.; Grab, D.J.; McKerrow, J.H. RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. PLoS Negl. Trop. Dis., 2008, 2(9), e298.
59. Koopmann, R.; Cupelli, K.; Redecke, L.; Nass, K.; Deponte, D.P.; White, T.A.; Stellato, F.; Rehders, D.; Liang, M.; Andreasson, J.; Aquila, A.; Bajt, S.; Barthelmess, M.; Barty, A.; Bogan, M.J.; Bostedt, C.; Boutet, S.; Bozek, J.D.; Caleman, C.; Coppola, N.; Davidsson, J.; Doak, R.B.; Ekeberg, T.; Epp, S.W.; Erk, B.; Fleckenstein, H.; Foucar, L.; Graafsma, H.; Gumprecht, L.; Hajdu, J.; Hampton, C.Y.; Hartmann, A.; Hartmann, R.; Hauser, G.; Hirsemann, H.; Holl, P.; Hunter, M.S.; Kassemeyer, S.; Kirian, R.A.; Lomb, L.; Maia, F.R.; Kimmel, N.; Martin, A.V.; Messerschmidt, M.; Reich, C.; Rolles, D.; Rudek, B.; Rudenko, A.; Schlichting, I.; Schulz, J.; Seibert, M.M.; Shoeman, R.L.; Sierra, R.G.; Soltau, H.; Stern, S.; Struder, L.; Timneanu, N.; Ullrich, J.; Wang, X.; Weidenspointner, G.; Weierstall, U.; Williams, G.J.; Wunderer, C.B.; Fromme, P.; Spence, J.C.; Stehle, T.; Chapman, H.N.; Betzel, C.; Duszenko, M. In vivo protein crystallization opens new routes in structural biology. Nat. Meth., 2012, 9(3), 259-262.
60. Redecke, L.; Nass, K.; DePonte, D.P.; White, T.A.; Rehders, D.; Barty, A.; Stellato, F.; Liang, M.; Barends, T.R.; Boutet, S.; Williams, G.J.; Messerschmidt, M.; Seibert, M.M.; Aquila, A.; Arnlund, D.; Bajt, S.; Barth, T.; Bogan, M.J.; Caleman, C.; Chao, T.C.; Doak, R.B.; Fleckenstein, H.; Frank, M.; Fromme, R.; Galli, L.; Grotjohann, I.; Hunter, M.S.; Johansson, L.C.; Kassemeyer, S.; Katona, G.; Kirian, R.A.; Koopmann, R.; Kupitz, C.; Lomb, L.; Martin, A.V.; Mogk, S.; Neutze, R.; Shoeman, R.L.; Steinbrener, J.; Timneanu, N.; Wang, D.; Weierstall, U.; Zatsepin, N.A.; Spence, J.C.; Fromme, P.; Schlichting, I.; Duszenko, M.; Betzel, C.; Chapman, H.N. Natively inhibited Trypanosoma brucei cathepsin B structure determined by using an X-ray laser. Science, 2013, 339(6116), 227-230.
61. Newman, D.J.; Cragg, G.M.; Snader, K.M. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod., 2003, 66(7), 1022-1037.
62. Tagboto, S.; Townson, S. Antiparasitic properties of medicinal plants and other naturally occurring products. Adv. Parasitol., 2001, 50, 199-295.
63. 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(3), 353-364.
64. Schmidt, T.J.; Khalid, S.A.; Romanha, A.J.; Alves, T.M.; Biavatti, M.W.; Brun, R.; Da Costa, F.B.; de Castro, S.L.; Ferreira, V.F.; de Lacerda, M.V.; Lago, J.H.; Leon, L.L.; Lopes, N.P.; das Neves Amorim, R.C.; Niehues, M.; Ogungbe, I.V.; Pohlit, A.M.; Scotti, M.T.; Setzer, W.N.; de, N.C.S.M.; Steindel, M.; Tempone, A.G. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I. Curr. Med. Chem., 2012, 19(14), 2128-2175.
65. Takabatake, Y.; Isaka, Y.; Mizui, M.; Kawachi, H.; Shimizu, F.; Ito, T.; Hori, M.; Imai, E. Exploring RNA interference as a therapeutic strategy for renal disease. Gene Ther., 2005, 12(12), 965-973.
66. Chothia, C. Proteins. One thousand families for the molecular biologist. Nature, 1992, 357(6379), 543-544.
67. Anantharaman, V.; Aravind, L.; Koonin, E.V. Emergence of diverse biochemical activities in evolutionarily conserved structural scaffolds of proteins. Curr. Opin. Chem. Biol., 2003, 7(1), 12-20.
68. Breinbauer, R.; Vetter, I.R.; Waldmann, H. From protein domains to drug candidates- natural products as guiding principles in the design and synthesis of compound libraries. Angewandte Chemie, 2002, 41(16), 2879-2890.
69. Saccharomyces Genome Database. www.yeastgenome.org (Accessed July 2013).
70. Herman, M.; Perez-Morga, D.; Schtickzelle, N.; Michels, P.A. Turnover of glycosomes during life-cycle differentiation of Trypanosoma brucei. Autophagy, 2008, 4(3), 294-308.
71. Chen, Y.; Klionsky, D.J. The regulation of autophagy - unanswered questions. J. Cell Sci., 2011, 124(Pt 2), 161-170.
72. Hall, M.N. mTOR-what does it do? Transplant. Proc., 2008, 40(10 Suppl), S5-S8.
73. Nakatogawa, H.; Suzuki, K.; Kamada, Y.; Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol., 2009, 10(7), 458-467.
74. Schmidt, A.; Kunz, J.; Hall, M.N. TOR2 is required for organization of the actin cytoskeleton in yeast. Proc. Natl. Acad. Sci. U. S. A., 1996, 93(24), 13780-13785.
75. Sarbassov, D.D.; Ali, S.M.; Kim, D.H.; Guertin, D.A.; Latek, R.R.; Erdjument- Bromage, H.; Tempst, P.; Sabatini, D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol., 2004, 14(14), 1296-1302.
76. Geng, J.; Klionsky, D.J. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep., 2008, 9(9), 859-864.
77. Mizushima, N.; Yamamoto, A.; Hatano, M.; Kobayashi, Y.; Kabeya, Y.; Suzuki, K.; Tokuhisa, T.; Ohsumi, Y.; Yoshimori, T. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol., 2001, 152(4), 657-668.
78. Mizushima, N.; Kuma, A.; Kobayashi, Y.; Yamamoto, A.; Matsubae, M.; Takao, T.; Natsume, T.; Ohsumi, Y.; Yoshimori, T. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J. Cell Sci., 2003, 116(Pt 9), 1679-1688.
79. Kabeya, Y.; Mizushima, N.; Ueno, T.; Yamamoto, A.; Kirisako, T.; Noda, T.; Kominami, E.; Ohsumi, Y.; Yoshimori, T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO. J., 2000, 19(21), 5720-5728.
80. Yorimitsu, T.; Klionsky, D.J. Autophagy: molecular machinery for self-eating. Cell Death Differ., 2005, 12 Suppl 2, 1542-1552.
81. Herman, M.; Gillies, S.; Michels, P.A.; Rigden, D.J. Autophagy and related processes in trypanosomatids: insights from genomic and bioinformatic analyses. Autophagy, 2006, 2(2), 107-118.
82. Barquilla, A.; Crespo, J.L.; Navarro, M. Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation. Proc. Natl. Acad. Sci. U. S. A., 2008, 105(38), 14579-14584.
83. Hall, B.S.; Gabernet-Castello, C.; Voak, A.; Goulding, D.; Natesan, S.K.; Field, M.C. TbVps34, the trypanosome orthologue of Vps34, is required for Golgi complex segregation. J. Biol. Chem., 2006, 281(37), 27600-27612.
84. Alvarez, V.E.; Kosec, G.; Sant'Anna, C.; Turk, V.; Cazzulo, J.J.; Turk, B. Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi. J. Biol. Chem., 2008, 283(6), 3454-3464.
85. Duszenko, M.; Ginger, M.L.; Brennand, A.; Gualdron-Lopez, M.; Colombo, M.I.; Coombs, G.H.; Coppens, I.; Jayabalasingham, B.; Langsley, G.; de Castro, S.L.; Menna-Barreto, R.; Mottram, J.C.; Navarro, M.; Rigden, D.J.; Romano, P.S.; Stoka, V.; Turk, B.; Michels, P.A. Autophagy in protists. Autophagy, 2011, 7(2), 127-158.
86. Koopmann, R.; Muhammad, K.; Perbandt, M.; Betzel, C.; Duszenko, M. Trypanosoma brucei ATG8: structural insights into autophagic-like mechanisms in protozoa. Autophagy, 2009, 5(8), 1085-1091.
87. Williams, R.A.; Mottram, J.C.; Coombs, G.H. Distinct roles in autophagy and importance in infectivity of the two ATG4 cysteine peptidases of Leishmania major. J. Biol. Chem., 2013, 288(5), 3678-3690.
88. Alvarez, V.E.; Kosec, G.; Sant Anna, C.; Turk, V.; Cazzulo, J.J.; Turk, B. Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections? Autophagy, 2008, 4(3), 361-363.
89. Brennand, A.; Gualdron-Lopez, M.; Coppens, I.; Rigden, D.J.; Ginger, M.L.; Michels, P.A. Autophagy in parasitic protists: unique features and drug targets. Mol. Biochem. Parasitol., 2011, 177(2), 83-99.
90. van Zandbergen, G.; Luder, C.G.; Heussler, V.; Duszenko, M. Programmed cell death in unicellular parasites: a prerequisite for sustained infection? Trends Parasitol., 2010, 26 (10), 477-483.
91. Piacenza, L.; Peluffo, G.; Radi, R. L-arginine-dependent suppression of apoptosis in Trypanosoma cruzi: contribution of the nitric oxide and polyamine pathways. Proc. Natl. Acad. Sci. U. S. A., 2001, 98(13), 7301-7306.
92. Das, M.; Mukherjee, S.B.; Shaha, C. Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. J. Cell Sci., 2001, 114(Pt 13), 2461-2469.
93. Vardi, A.; Berman-Frank, I.; Rozenberg, T.; Hadas, O.; Kaplan, A.; Levine, A. Programmed cell death of the dinoflagellate Peridinium gatunense is mediated by CO(2) limitation and oxidative stress. Curr. Biol., 1999, 9(18), 1061-1064.
94. Ridgley, E.L.; Xiong, Z.H.; Ruben, L. Reactive oxygen species activate a Ca2+- dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei. Biochem. J., 1999, 340( Pt 1), 33-40.
95. Lee, N.; Bertholet, S.; Debrabant, A.; Muller, J.; Duncan, R.; Nakhasi, H.L. Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ., 2002, 9(1), 53-64.
96. Zangger, H.; Mottram, J.C.; Fasel, N. Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis? Cell Death Differ., 2002, 9(10), 1126-1139.
97. Duszenko, M.; Figarella, K.; Macleod, E.T.; Welburn, S.C. Death of a trypanosome: a selfish altruism. Trends Parasitol., 2006, 22(11), 536-542.
98. Figarella, K.; Uzcategui, N.L.; Beck, A.; Schoenfeld, C.; Kubata, B.K.; Lang, F.; Duszenko, M. Prostaglandin-induced programmed cell death in Trypanosoma brucei involves oxidative stress. Cell Death Differ., 2006, 13(10), 1802-1814.
99. Rico, E.; Alzate, J.F.; Arias, A.A.; Moreno, D.; Clos, J.; Gago, F.; Moreno, I.; Dominguez, M.; Jimenez-Ruiz, A. Leishmania infantum expresses a mitochondrial nuclease homologous to EndoG that migrates to the nucleus in response to an apoptotic stimulus. Mol. Biochem. Parasitol., 2009, 163(1), 28-38.
100. Broker, L.E.; Kruyt, F.A.; Giaccone, G. Cell death independent of caspases: a review. Clin. Canc. Res., 2005, 11(9), 3155-3162.
101. Metcalf, P.; Blum, M.; Freymann, D.; Turner, M.; Wiley, D.C. Two variant surface glycoproteins of Trypanosoma brucei of different sequence classes have similar 6 A resolution X-ray structures. Nature, 1987, 325(6099), 84-86.
102. Barth, T.; Stein, J.; Mogk, S.; Schönfeld, C.; Kubata, B.; Duszenko, M. Trypanosomatid Diseases: Life and Death of Trypanosoma brucei: New Perspectives for Drug Development. Wiley- Blackwell, 2013, ISBN: 978-3-527-33255-7
103. Ollivier, G.; Legros, D. [Human african trypanosomiasis: A history of its therapies and their failures]. Trop. Med. Int. Health, 2001, 6(11), 855-863.
104. Eckart, W. Illustrierte Geschichte der Medizin. Springer, 2010, ISBN: 978-3642126093
105. Ehrlich, P. Abhandlungen zu Salvarsan. J. F. Lehmanns, 1911-1914
106. Fairlamb, A.H. Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol., 2003, 19(11), 488-494.
107. Castro, J.A.; de Mecca, M.M.; Bartel, L.C. Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis). Hum. Exp. Toxicol., 2006, 25(8), 471-479.
108. Pepin, J.; Milord, F.; Meurice, F.; Ethier, L.; Loko, L.; Mpia, B. High-dose nifurtimox for arseno-resistant. Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire. Trans. R. Soc. Trop. Med. Hyg., 1992, 86(3), 254-256.
109. Torreele, E.; Bourdin Trunz, B.; Tweats, D.; Kaiser, M.; Brun, R.; Mazue, G.; Bray, M.A.; Pecoul, B. Fexinidazole-a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl. Trop. Dis., 2010, 4(12), e923.