Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-09T22:49:58.428Z Has data issue: false hasContentIssue false

Trypanocidal drugs: mechanisms, resistance and new targets

Published online by Cambridge University Press:  29 October 2009

Shane R. Wilkinson*
Affiliation:
Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK.
John M. Kelly
Affiliation:
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
*
*Corresponding author: Shane Wilkinson, School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK. Tel: +44 (0)207 882 3057; Fax: +44 (0)20 8983 0973; E-mail: [email protected]

Abstract

The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi are the causative agents of African trypanosomiasis and Chagas disease, respectively. These are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. Treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. Here, we review the properties of these drugs and describe new findings on their modes of action and the mechanisms by which resistance can arise. We further outline how a greater understanding of parasite biology is being exploited in the search for novel chemotherapeutic agents. This effort is being facilitated by new research networks that involve academic and biotechnology/pharmaceutical organisations, supported by public–private partnerships, and are bringing a new dynamism and purpose to the search for trypanocidal agents.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Steverding, D. (2008) The history of African trypanosomiasis. Parasites and Vectors 1, 3CrossRefGoogle ScholarPubMed
2Barrett, M.P. et al. (2003) The trypanosomiases. Lancet 362, 1469-1480CrossRefGoogle ScholarPubMed
3Stuart, K. et al. (2008) Kinetoplastids: related protozoan pathogens, different diseases. Journal of Clinical Investigation 118, 1301-1310CrossRefGoogle ScholarPubMed
4Barrett, M.P. (2006) The rise and fall of sleeping sickness. Lancet 367, 1377-1378CrossRefGoogle ScholarPubMed
5Matovu, E. et al. (2001) Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy. Molecular and Biochemical Parasitology 117, 73-81CrossRefGoogle ScholarPubMed
6Checchi, F. et al. (2007) Nifurtimox plus eflornithine for late-stage sleeping sickness in Uganda: a case series. PLoS Neglected Tropical Diseases 1, e64CrossRefGoogle ScholarPubMed
7Priotto, G. et al. (2006) Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clinical Trials 1, e39CrossRefGoogle ScholarPubMed
8Priotto, G. et al. (2009) Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 374, 56-64CrossRefGoogle ScholarPubMed
9Docampo, R. and Moreno, S.N. (2003) Current chemotherapy of human African trypanosomiasis. Parasitology Research 90, S10-13CrossRefGoogle ScholarPubMed
10Nok, A.J. (2003) Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis. Parasitology Research 90, 71-79CrossRefGoogle ScholarPubMed
11Legros, D. et al. (2002) Treatment of human African trypanosomiasis–present situation and needs for research and development. Lancet Infectious Diseases 2, 437-440CrossRefGoogle ScholarPubMed
12Spinks, A. (1948) The persistence in the blood stream of some compounds related to suramin. Biochemical Journal 42, 109-116CrossRefGoogle ScholarPubMed
13Fairlamb, A.H. and Bowman, I.B. (1980) Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo. Molecular and Biochemical Parasitology 1, 315-333CrossRefGoogle ScholarPubMed
14Coppens, I. et al. (1987) Receptor-mediated endocytosis in the bloodstream form of Trypanosoma brucei. Journal of Protozoology 34, 465-473CrossRefGoogle ScholarPubMed
15Vansterkenburg, E.L. et al. (1993) The uptake of the trypanocidal drug suramin in combination with low-density lipoproteins by Trypanosoma brucei and its possible mode of action. Acta Tropica 54, 237-250CrossRefGoogle ScholarPubMed
16Pal, A., Hall, B.S. and Field, M.C. (2002) Evidence for a non-LDL-mediated entry route for the trypanocidal drug suramin in Trypanosoma brucei. Molecular and Biochemical Parasitology 122, 217-221CrossRefGoogle ScholarPubMed
17Scott, A.G., Tait, A. and Turner, C.M. (1996) Characterisation of cloned lines of Trypanosoma brucei expressing stable resistance to MelCy and suramin. Acta Tropica 60, 251-262CrossRefGoogle ScholarPubMed
18Mutugi, M.W., Boid, R. and Luckins, A.G. (1994) Experimental induction of suramin-resistance in cloned and uncloned stocks of Trypanosoma evansi using immunosuppressed and immunocompetent mice. Tropical Medicine and Parasitology 45, 232-236Google ScholarPubMed
19Misset, O. and Opperdoes, F.R. (1987) The phosphoglycerate kinases from Trypanosoma brucei. A comparison of the glycosomal and the cytosolic isoenzymes and their sensitivity towards suramin. European Journal of Biochemistry 162, 493-500CrossRefGoogle ScholarPubMed
20Willson, M. et al. (1993) Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Molecular and Biochemical Parasitology 59, 201-210CrossRefGoogle ScholarPubMed
21Conte, J.E. Jr, Upton, R.A. and Lin, E.T. (1987) Pentamidine pharmacokinetics in patients with AIDS with impaired renal function. Journal of Infectious Diseases 156, 885-890CrossRefGoogle ScholarPubMed
22Berger, B.J. et al. (1992) Primary and secondary metabolism of pentamidine by rats. Antimicrobial Agents and Chemotherapy 36, 1825-1831CrossRefGoogle ScholarPubMed
23Berger, B.J. and Fairlamb, A.H. (1993) Cytochrome P450 in trypanosomatids. Biochemical Pharmacology 46, 149-157CrossRefGoogle ScholarPubMed
24Sanderson, L. et al. (2009) Pentamidine movement across the murine blood-brain and blood-cerebrospinal fluid barriers: effect of trypanosome infection, combination therapy, P-glycoprotein, and multidrug resistance-associated protein. Journal of Pharmacology and Experimental Therapeutics 329, 967-977CrossRefGoogle ScholarPubMed
25Carter, N.S., Berger, B.J. and Fairlamb, A.H. (1995) Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei. Journal of Biological Chemistry 270, 28153-28157CrossRefGoogle ScholarPubMed
26de Koning, H.P., and Jarvis, S.M. (2001) Uptake of pentamidine in Trypanosoma brucei brucei is mediated by the P2 adenosine transporter and at least one novel, unrelated transporter. Acta Tropica 80, 245-250CrossRefGoogle ScholarPubMed
27Berger, B.J., Carter, N.S. and Fairlamb, A.H. (1995) Characterisation of pentamidine-resistant Trypanosoma brucei brucei. Molecular and Biochemical Parasitology 69, 289-298CrossRefGoogle ScholarPubMed
28Matovu, E. et al. (2003) Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryotic Cell 2, 1003-1008CrossRefGoogle ScholarPubMed
29De Koning, H.P. (2001) Uptake of pentamidine in Trypanosoma brucei brucei is mediated by three distinct transporters: implications for cross-resistance with arsenicals. Molecular Pharmacology 59, 586-592CrossRefGoogle ScholarPubMed
30Bridges, D.J. et al. (2007) Loss of the high-affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Molecular Pharmacology 71, 1098-1108CrossRefGoogle ScholarPubMed
31Wilson, W.D. et al. (2008) Antiparasitic compounds that target DNA. Biochimie 90, 999-1014CrossRefGoogle ScholarPubMed
32Mathis, A.M. et al. (2006) Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes. Antimicrobial Agents and Chemotherapy 50, 2185-2191CrossRefGoogle ScholarPubMed
33Shapiro, T.A. and Englund, P.T. (1990) Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proceedings of the National Academy of Sciences of the United States of America 87, 950-954CrossRefGoogle ScholarPubMed
34Wang, C.C. (1995) Molecular mechanisms and therapeutic approaches to the treatment of African trypanosomiasis. Annual Review of Pharmacology and Toxicology 35, 93-127CrossRefGoogle Scholar
35Bitonti, A.J., Dumont, J.A. and McCann, P.P. (1986) Characterization of Trypanosoma brucei brucei S-adenosyl-L-methionine decarboxylase and its inhibition by Berenil, pentamidine and methylglyoxal bis(guanylhydrazone). Biochemical Journal 237, 685-689CrossRefGoogle ScholarPubMed
36Benaim, G. et al. (1993) A calmodulin-stimulated Ca2+ pump in plasma-membrane vesicles from Trypanosoma brucei; selective inhibition by pentamidine. Biochemical Journal 296, 759-763CrossRefGoogle ScholarPubMed
37Vercesi, A.E. and Docampo, R. (1992) Ca2+ transport by digitonin-permeabilized Leishmania donovani. Effects of Ca2+, pentamidine and WR-6026 on mitochondrial membrane potential in situ. Biochemical Journal 284, 463-467CrossRefGoogle ScholarPubMed
38Moreno, S.N. (1996) Pentamidine is an uncoupler of oxidative phosphorylation in rat liver mitochondria. Archives of Biochemistry and Biophysics 326, 15-20CrossRefGoogle ScholarPubMed
39Friedheim, E.A. (1949) Mel B in the treatment of human trypanosomiasis. American Journal of Tropical Medicine and Hygiene 29, 173-180CrossRefGoogle ScholarPubMed
40Enanga, B. et al. (2002) Sleeping sickness and the brain. Cellular and Molecular Life Sciences 59, 845-858CrossRefGoogle ScholarPubMed
41Blum, J. and Burri, C. (2002) Treatment of late stage sleeping sickness caused by T.b. gambiense: a new approach to the use of an old drug. Swiss Medical Weekly 132, 51-56Google Scholar
42Burri, C. et al. (1993) Pharmacokinetic properties of the trypanocidal drug melarsoprol. Chemotherapy 39, 225-234CrossRefGoogle ScholarPubMed
43Carter, N.S. and Fairlamb, A.H. (1993) Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 361, 173-176CrossRefGoogle ScholarPubMed
44Maser, P. et al. (1999) A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science 285, 242-244CrossRefGoogle ScholarPubMed
45Barrett, M.P. and Fairlamb, A.H. (1999) The biochemical basis of arsenical-diamidine crossresistance in African trypanosomes. Parasitology Today 15, 136-140CrossRefGoogle ScholarPubMed
46Tye, C.K. et al. (1998) An approach to use an unusual adenosine transporter to selectively deliver polyamine analogues to trypanosomes. Bioorganic and Medicinal Chemistry Letters 8, 811-816CrossRefGoogle ScholarPubMed
47de Koning, H.P. and Jarvis, S.M. (1999) Adenosine transporters in bloodstream forms of Trypanosoma brucei brucei: substrate recognition motifs and affinity for trypanocidal drugs. Molecular Pharmacology 56, 1162-1170CrossRefGoogle ScholarPubMed
48de Koning, H.P. (2001) Transporters in African trypanosomes: role in drug action and resistance. International Journal of Parasitology 31, 512-522CrossRefGoogle ScholarPubMed
49Baliani, A. et al. (2005) Design and synthesis of a series of melamine-based nitroheterocycles with activity against Trypanosomatid parasites. Journal of Medicinal Chemistry 48, 5570-5579CrossRefGoogle ScholarPubMed
50Stewart, M.L. et al. (2004) Trypanocidal activity of melamine-based nitroheterocycles. Antimicrobial Agents and Chemotherapy 48, 1733-1738CrossRefGoogle ScholarPubMed
51Baliani, A. et al. (2009) Novel functionalized melamine-based nitroheterocycles: synthesis and activity against trypanosomatid parasites. Organic and Biomolecular Chemistry 7, 1154-1166CrossRefGoogle ScholarPubMed
52Chollet, C. et al. (2009) Targeted delivery of compounds to Trypanosoma brucei using the melamine motif. Bioorganic and Medicinal Chemistry 17, 2512-2523CrossRefGoogle ScholarPubMed
53Fairlamb, A.H. et al. (1992) Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism. Molecular and Biochemical Parasitology 53, 213-222CrossRefGoogle ScholarPubMed
54de Koning, H.P. (2008) Ever-increasing complexities of diamidine and arsenical crossresistance in African trypanosomes. Trends in Parasitology 24, 345-349CrossRefGoogle ScholarPubMed
55Van Schaftingen, E., Opperdoes, F.R. and Hers, H.G. (1987) Effects of various metabolic conditions and of the trivalent arsenical melarsen oxide on the intracellular levels of fructose 2,6-bisphosphate and of glycolytic intermediates in Trypanosoma brucei. European Journal of Biochemistry 166, 653-661CrossRefGoogle ScholarPubMed
56Hanau, S. et al. (1996) 6-Phosphogluconate dehydrogenase from Trypanosoma brucei. Kinetic analysis and inhibition by trypanocidal drugs. European Journal of Biochemistry 240, 592-599CrossRefGoogle ScholarPubMed
57Fairlamb, A.H. et al. (1985) Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science 227, 1485-1487CrossRefGoogle ScholarPubMed
58Fairlamb, A.H., Henderson, G.B. and Cerami, A. (1989) Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proceedings of the National Academy of Sciences of the United States of America 86, 2607-2611CrossRefGoogle ScholarPubMed
59Cunningham, M.L., Zvelebil, M.J. and Fairlamb, A.H. (1994) Mechanism of inhibition of trypanothione reductase and glutathione reductase by trivalent organic arsenicals. European Journal of Biochemistry 221, 285-295CrossRefGoogle ScholarPubMed
60Krieger, S. et al. (2000) Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Molecular Microbiology 35, 542-552CrossRefGoogle ScholarPubMed
61Sauvage, V. et al. The role of ATP-Binding Cassette (ABC) proteins in protozoan parasites. Molecular and Biochemical Parasitology 167, 81-94CrossRefGoogle Scholar
62Shahi, S.K., Krauth-Siegel, R.L. and Clayton, C.E. (2002) Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Molecular Microbiology 43, 1129-1138CrossRefGoogle ScholarPubMed
63Alibu, V.P. et al. (2006) The role of Trypanosoma brucei MRPA in melarsoprol susceptibility. Molecular and Biochemical Parasitology 146, 38-44CrossRefGoogle ScholarPubMed
64Bacchi, C.J. et al. (1980) Polyamine metabolism: a potential therapeutic target in trypanosomes. Science 210, 332-334CrossRefGoogle ScholarPubMed
65Robays, J. et al. (2008) Eflornithine is a cost-effective alternative to melarsoprol for the treatment of second-stage human West African trypanosomiasis in Caxito, Angola. Tropical Medicine and International Health 13, 265-271CrossRefGoogle ScholarPubMed
66Sanderson, L. et al. (2008) The blood-brain barrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain. Journal of Neurochemistry 107, 1136-1146CrossRefGoogle ScholarPubMed
67Balasegaram, M. et al. (2009) Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Medecins Sans Frontieres programmes. Transactions of the Royal Society of Tropical Medicine and Hygiene 103, 280-290CrossRefGoogle Scholar
68Politi, C. et al. (1995) Cost-effectiveness analysis of alternative treatments of African gambiense trypanosomiasis in Uganda. Health Eeconomics 4, 273-287CrossRefGoogle ScholarPubMed
69Chappuis, F. et al. (2005) Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clinical Infectious Diseases 41, 748-751CrossRefGoogle ScholarPubMed
70Bellofatto, V. et al. (1987) Biochemical changes associated with alpha-difluoromethylornithine uptake and resistance in Trypanosoma brucei. Molecular and Biochemical Parasitology 25, 227-238CrossRefGoogle ScholarPubMed
71Erwin, B.G. and Pegg, A.E. (1982) Uptake of alpha-difluoromethylornithine by mouse fibroblasts. Biochemical Pharmacology 31, 2820-2823CrossRefGoogle ScholarPubMed
72Bitonti, A.J. et al. (1986) Uptake of alpha-difluoromethylornithine by Trypanosoma brucei brucei. Biochemical Pharmacology 35, 351-354CrossRefGoogle ScholarPubMed
73Phillips, M.A. and Wang, C.C. (1987) A Trypanosoma brucei mutant resistant to alpha-difluoromethylornithine. Molecular and Biochemical Parasitology 22, 9-17CrossRefGoogle ScholarPubMed
74Willert, E.K. and Phillips, M.A. (2008) Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes. PLoS Pathogens 4, e1000183CrossRefGoogle ScholarPubMed
75Phillips, M.A., Coffino, P. and Wang, C.C. (1987) Cloning and sequencing of the ornithine decarboxylase gene from Trypanosoma brucei. Implications for enzyme turnover and selective difluoromethylornithine inhibition. Journal of Biological Chemistry 262, 8721-8727CrossRefGoogle ScholarPubMed
76Ghoda, L. et al. (1990) Trypanosome ornithine decarboxylase is stable because it lacks sequences found in the carboxyl terminus of the mouse enzyme which target the latter for intracellular degradation. Journal of Biological Chemistry 265, 11823-11826CrossRefGoogle ScholarPubMed
77Tabor, C.W. and Tabor, H. (1984) Polyamines. Annual Review of Biochemistry 53, 749-790CrossRefGoogle ScholarPubMed
78Iten, M. et al. (1997) Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-alpha-difluoromethylornithine. Antimicrobial Agents and Chemotherapy 41, 1922-1925CrossRefGoogle ScholarPubMed
79Schofield, C.J., Jannin, J. and Salvatella, R. (2006) The future of Chagas disease control. Trends in Parasitology 22, 583-588CrossRefGoogle ScholarPubMed
80Bern, C. et al. (2007) Evaluation and treatment of Chagas disease in the United States: a systematic review. Journal of the American Medical Association 298, 2171-2181CrossRefGoogle ScholarPubMed
81Diazgranados, C.A. et al. (2009) Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association. Lancet Infectious Diseases 9, 324-330CrossRefGoogle ScholarPubMed
82Dias, J.C., Silveira, A.C. and Schofield, C.J. (2002) The impact of Chagas disease control in Latin America: a review. Memorias do Instituto Oswaldo Cruz 97, 603-612CrossRefGoogle ScholarPubMed
83Rodriques Coura, J. and de Castro, S.L. (2002) A critical review on Chagas disease chemotherapy. Memorias do Instituto Oswaldo Cruz 97, 3-24CrossRefGoogle ScholarPubMed
84Gorla, N.B. et al. (1989) Thirteenfold increase of chromosomal aberrations non-randomly distributed in chagasic children treated with nifurtimox. Mutation Research 224, 263-267CrossRefGoogle ScholarPubMed
85Ferreira, R.C., Schwarz, U. and Ferreira, L.C. (1988) Activation of anti-Trypanosoma cruzi drugs to genotoxic metabolites promoted by mammalian microsomal enzymes. Mutation Research 204, 577-583CrossRefGoogle ScholarPubMed
86Kalil, J. and Cunha-Neto, E. (1996) Autoimmunity in chagas disease cardiomyopathy: Fulfilling the criteria at last? Parasitology Today 12, 396-399CrossRefGoogle ScholarPubMed
87Tarleton, R.L., Zhang, L. and Downs, M.O. (1997) “Autoimmune rejection” of neonatal heart transplants in experimental Chagas disease is a parasite-specific response to infected host tissue. Proceedings of the National Academy of Sciences of the United States of America 94, 3932-3937CrossRefGoogle ScholarPubMed
88Tarleton, R.L. and Zhang, L. (1999) Chagas disease etiology: autoimmunity or parasite persistence? Parasitology Today 15, 94-99CrossRefGoogle ScholarPubMed
89Tarleton, R.L. (2003) Chagas disease: a role for autoimmunity? Trends in Parasitology 19, 447-451CrossRefGoogle ScholarPubMed
90Garcia, S. et al. (2005) Treatment with benznidazole during the chronic phase of experimental Chagas' disease decreases cardiac alterations. Antimicrobial Agents and Chemotherapy 49, 1521-1528CrossRefGoogle ScholarPubMed
91Bustamante, J.M., Bixby, L.M. and Tarleton, R.L. (2008) Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nature Medicine 14, 542-550CrossRefGoogle ScholarPubMed
92Walton, M.I. and Workman, P. (1987) Nitroimidazole bioreductive metabolism. Quantitation and characterisation of mouse tissue benznidazole nitroreductases in vivo and in vitro. Biochemical Pharmacology 36, 887-896CrossRefGoogle ScholarPubMed
93Montalto de Mecca, M., Diaz, E.G. and Castro, J.A. (2002) Nifurtimox biotransformation to reactive metabolites or nitrite in liver subcellular fractions and model systems. Toxicology Letters 136, 1-8CrossRefGoogle ScholarPubMed
94Mecca, M.M. et al. (2008) Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects. Memorias do Instituto Oswaldo Cruz 103, 549-553CrossRefGoogle ScholarPubMed
95Raether, W. and Hanel, H. (2003) Nitroheterocyclic drugs with broad spectrum activity. Parasitology Research 90, S19-39CrossRefGoogle ScholarPubMed
96Docampo, R. (1990) Sensitivity of parasites to free radical damage by antiparasitic drugs. Chemico-Biological Interactions 73, 1-27CrossRefGoogle ScholarPubMed
97Docampo, R. et al. (1981) Generation of free radicals induced by nifurtimox in mammalian tissues. Journal of Biological Chemistry 256, 10930-10933CrossRefGoogle ScholarPubMed
98Viode, C. et al. (1999) Enzymatic reduction studies of nitroheterocycles. Biochemical Pharmacology 57, 549-557CrossRefGoogle ScholarPubMed
99Henderson, G.B. et al. (1988) “Subversive” substrates for the enzyme trypanothione disulfide reductase: alternative approach to chemotherapy of Chagas disease. Proceedings of the National Academy of Sciences of the United States of America 85, 5374-5378CrossRefGoogle ScholarPubMed
100Blumenstiel, K. et al. (1999) Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase. Biochemical Pharmacology 58, 1791-1799CrossRefGoogle ScholarPubMed
101Boveris, A. et al. (1980) Deficient metabolic utilization of hydrogen peroxide in Trypanosoma cruzi. Biochemical Journal 188, 643-648CrossRefGoogle ScholarPubMed
102Fairlamb, A.H. and Cerami, A. (1992) Metabolism and functions of trypanothione in the Kinetoplastida. Annual Review of Microbiology 46, 695-729CrossRefGoogle ScholarPubMed
103Flohe, L., Hecht, H.J. and Steinert, P. (1999) Glutathione and trypanothione in parasitic hydroperoxide metabolism. Free Radical Biology and Medicine 27, 966-984CrossRefGoogle ScholarPubMed
104Wilkinson, S.R. et al. (2002) Trypanosoma cruzi expresses a plant-like ascorbate-dependent hemoperoxidase localized to the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 99, 13453-13458CrossRefGoogle ScholarPubMed
105Wilkinson, S.R. and Kelly, J.M. (2003) The role of glutathione peroxidases in trypanosomatids. Biological Chemistry 384, 517-525CrossRefGoogle ScholarPubMed
106Irigoín, F. et al. (2008) Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification. Free Radical Biology and Medicine 45, 733-742CrossRefGoogle ScholarPubMed
107Prathalingham, S.R. et al. (2007) Deletion of the Trypanosoma brucei superoxide dismutase gene sodb1 increases sensitivity to nifurtimox and benznidazole. Antimicrobial Agents and Chemotherapy 51, 755-758CrossRefGoogle ScholarPubMed
108Wilkinson, S.R. et al. (2000) Distinct mitochondrial and cytosolic enzymes mediate trypanothione-dependent peroxide metabolism in Trypanosoma cruzi. Journal of Biological Chemistry 275, 8220-8225CrossRefGoogle ScholarPubMed
109Wilkinson, S.R. et al. (2002) The Trypanosoma cruzi enzyme TcGPXI is a glycosomal peroxidase and can be linked to trypanothione reduction by glutathione or tryparedoxin. Journal of Biological Chemistry 277, 17062-17071CrossRefGoogle ScholarPubMed
110Wilkinson, S.R. et al. (2002) TcGPXII, a glutathione-dependent Trypanosoma cruzi peroxidase with substrate specificity restricted to fatty acid and phospholipid hydroperoxides, is localized to the endoplasmic reticulum. Biochemical Journal 364, 787-794CrossRefGoogle ScholarPubMed
111Wilkinson, S.R. et al. (2003) RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the African trypanosome. Journal of Biological Chemistry 278, 31640-13646CrossRefGoogle Scholar
112Wilkinson, S.R. et al. (2006) Functional characterisation of the iron superoxide dismutase gene repertoire in Trypanosoma brucei. Free Radical Biology and Medicine 40, 198-209CrossRefGoogle ScholarPubMed
113Kelly, J.M. et al. (1993) Phenotype of recombinant Leishmania donovani and Trypanosoma cruzi which over-express trypanothione reductase. Sensitivity towards agents that are thought to induce oxidative stress. European Journal of Biochemistry 218, 29-37CrossRefGoogle ScholarPubMed
114Peterson, F.J. et al. (1979) Oxygen-sensitive and -insensitive nitroreduction by Escherichia coli and rat hepatic microsomes. Journal of Biological Chemistry 254, 4009-4014CrossRefGoogle ScholarPubMed
115Roldan, M.D. et al. (2008) Reduction of polynitroaromatic compounds: the bacterial nitroreductases. FEMS Microbiology Reviews 32, 474-500CrossRefGoogle ScholarPubMed
116McCalla, D.R., Reuvers, A. and Kaiser, C. (1971) Breakage of bacterial DNA by nitrofuran derivatives. Cancer Research 31, 2184-2188Google ScholarPubMed
117Streeter, A.J. and Hoener, B.A. (1988) Evidence for the involvement of a nitrenium ion in the covalent binding of nitrofurazone to DNA. Pharmaceutical Research 5, 434-436CrossRefGoogle ScholarPubMed
118Maya, J.D. et al. (1997) Effects of nifurtimox and benznidazole upon glutathione and trypanothione content in epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi. Molecular and Biochemical Parasitology 86, 101-106Google ScholarPubMed
119Kubata, B.K. et al. (2002) A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi. Journal of Experimental Medicine 196, 1241-1251CrossRefGoogle Scholar
120Wilkinson, S.R. et al. (2008) A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proceedings of the National Academy of Sciences of the United States of America 105, 5022-5027CrossRefGoogle ScholarPubMed
121Nozaki, T., Engel, J.C. and Dvorak, J.A. (1996) Cellular and molecular biological analyses of nifurtimox resistance in Trypanosoma cruzi. American Journal of Tropical Medicine and Hygiene 55, 111-117CrossRefGoogle ScholarPubMed
122Murta, S.M. and Romanha, A.J. (1998) In vivo selection of a population of Trypanosoma cruzi and clones resistant to benznidazole. Parasitology 116, 165-171CrossRefGoogle ScholarPubMed
123Nogueira, F.B. et al. (2006) Increased expression of iron-containing superoxide dismutase-A (TcFeSOD-A) enzyme in Trypanosoma cruzi population with in vitro-induced resistance to benznidazole. Acta Tropica 100, 119-132CrossRefGoogle ScholarPubMed
124Murta, S.M. et al. (2006) Deletion of copies of the gene encoding old yellow enzyme (TcOYE), a NAD(P)H flavin oxidoreductase, associates with in vitro-induced benznidazole resistance in Trypanosoma cruzi. Molecular and Biochemical Parasitology 146, 151-162CrossRefGoogle ScholarPubMed
125Murta, S.M. et al. (2008) Differential gene expression in Trypanosoma cruzi populations susceptible and resistant to benznidazole. Acta Tropica 107, 59-65CrossRefGoogle ScholarPubMed
126Andrade, H.M. et al. (2008) Proteomic analysis of Trypanosoma cruzi resistance to Benznidazole. Journal of Proteome Research 7, 2357-2367CrossRefGoogle ScholarPubMed
127Rego, J.V. et al. (2008) Trypanosoma cruzi: characterisation of the gene encoding tyrosine aminotransferase in benznidazole-resistant and susceptible populations. Experimental Parasitology 118, 111-117CrossRefGoogle ScholarPubMed
128Campos, F.M. et al. (2009) Characterization of a gene encoding alcohol dehydrogenase in benznidazole-susceptible and-resistant populations of Trypanosoma cruzi. Acta Tropica 111, 56-63CrossRefGoogle ScholarPubMed
129Nogueira, F.B. et al. (2009) Molecular characterization of cytosolic and mitochondrial tryparedoxin peroxidase in Trypanosoma cruzi populations susceptible and resistant to benznidazole. Parasitology Research 104, 835-844CrossRefGoogle ScholarPubMed
130Portal, P. et al. (2008) Multiple NADPH-cytochrome P450 reductases from Trypanosoma cruzi suggested role on drug resistance. Molecular and Biochemical Parasitology 160, 42-51CrossRefGoogle ScholarPubMed
131El-Sayed, N.M. et al. (2005) Comparative genomics of trypanosomatid parasitic protozoa. Science 309, 404-409CrossRefGoogle ScholarPubMed
132Berriman, M. et al. (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309, 416-422CrossRefGoogle ScholarPubMed
133Meissner, M., Agop-Nersesian, C. and Sullivan, W.J. Jr, (2007) Molecular tools for analysis of gene function in parasitic microorganisms. Applied Microbiology and Biotechnology 75, 963-975CrossRefGoogle ScholarPubMed
134Motyka, S.A. and Englund, P.T. (2004) RNA interference for analysis of gene function in trypanosomatids. Current Opinion in Microbiology 7, 362-368CrossRefGoogle ScholarPubMed
135Furlong, S.T. (1989) Sterols of parasitic protozoa and helminths. Experimental Parasitology 68, 482-485CrossRefGoogle ScholarPubMed
136Buckner, F. et al. (2003) A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents. Proceedings of the National Academy of Sciences of the United States of America 100, 15149-15153CrossRefGoogle ScholarPubMed
137Buckner, F.S. et al. (2003) Cloning and analysis of Trypanosoma cruzi lanosterol 14alpha-demethylase. Molecular and Biochemical Parasitology 132, 75-81CrossRefGoogle ScholarPubMed
138Buckner, F.S. et al. (2001) Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors. Antimicrobial Agents and Chemotherapy 45, 1210-1205CrossRefGoogle ScholarPubMed
139Urbina, J.A. et al. (2002) Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana. Molecular and Biochemical Parasitology 125, 35-45CrossRefGoogle ScholarPubMed
140Lepesheva, G.I. et al. (2007) Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chemistry and Biology 14, 1283-1293CrossRefGoogle ScholarPubMed
141Chen, C.K. et al. (2009) Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit. PLoS Neglected Tropical Diseases 3, e372CrossRefGoogle ScholarPubMed
142Konkle, M.E. et al. (2009) Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase. Journal of Medicinal Chemistry 52, 2846-2853CrossRefGoogle ScholarPubMed
143Coppens, I. and Courtoy, P.J. (2000) The adaptative mechanisms of Trypanosoma brucei for sterol homeostasis in its different life-cycle environments. Annual Review of Microbiology 54, 129-156CrossRefGoogle ScholarPubMed
144Urbina, J.A. and Docampo, R. (2003) Specific chemotherapy of Chagas disease: controversies and advances. Trends in Parasitology 19, 495-501CrossRefGoogle ScholarPubMed
145Roberts, C.W. et al. (2003) Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa. Molecular and Biochemical Parasitology 126, 129-142CrossRefGoogle ScholarPubMed
146Urbina, J.A. (2009) Ergosterol biosynthesis and drug development for Chagas disease. Memorias do Instituto Oswaldo Cruz 104, 311-318CrossRefGoogle ScholarPubMed
147Hucke, O. et al. (2005) The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease. Journal of Medicinal Chemistry 48, 5415-5418CrossRefGoogle ScholarPubMed
148Suryadevara, P.K. et al. (2009) Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease. Journal of Medicinal Chemistry 52, 3703-3715CrossRefGoogle Scholar
149Kraus, J.M. et al. (2009) Rational modification of a candidate cancer drug for use against Chagas disease. Journal of Medicinal Chemistry 52, 1639-1647CrossRefGoogle ScholarPubMed
150McKerrow, J.H. et al. (2009) Two approaches to discovering and developing new drugs for Chagas disease. Memorias do Instituto Oswaldo Cruz 104, 263-269CrossRefGoogle ScholarPubMed
151Molina, J. et al. (2000) In vivo activity of the bis-triazole D0870 against drug-susceptible and drug-resistant strains of the protozoan parasite Trypanosoma cruzi. Journal of Antimicrobial Chemotherapy 46, 137-140CrossRefGoogle ScholarPubMed
152Urbina, J.A. et al. (2003) Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. International Journal of Antimicrobial Agents 21, 39-48CrossRefGoogle ScholarPubMed
153Urbina, J.A. et al. (1988) Synergistic effects of ketoconazole and SF-86327 on the proliferation of epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Annals of the New York Academy of Sciences 544, 357-358CrossRefGoogle ScholarPubMed
154Gerpe, A. et al. (2008) Heteroallyl-containing 5-nitrofuranes as new anti-Trypanosoma cruzi agents with a dual mechanism of action. Bioorganic and Medicinal Chemistry 16, 569-577CrossRefGoogle ScholarPubMed
155Maldonado, R.A. et al. (1993) Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease. Antimicrobial Agents and Chemotherapy 37, 1353-1359CrossRefGoogle ScholarPubMed
156Hinshaw, J.C. et al. (2003) Oxidosqualene cyclase inhibitors as antimicrobial agents. Journal of Medicinal Chemistry 46, 4240-4243CrossRefGoogle ScholarPubMed
157Urbina, J.A. et al. (1995) Modification of the sterol composition of Trypanosoma (Schizotrypanum) cruzi epimastigotes by delta 24(25)-sterol methyl transferase inhibitors and their combinations with ketoconazole. Molecular and Biochemical Parasitology 73, 199-210CrossRefGoogle Scholar
158Urbina, J.A. et al. (1996) Antiproliferative effects of delta 24(25) sterol methyl transferase inhibitors on Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Chemotherapy 42, 294-307CrossRefGoogle Scholar
159Magaraci, F. et al. (2003) Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi. Journal of Medicinal Chemistry 46, 4714-4727CrossRefGoogle ScholarPubMed
160Lorente, S.O. et al. (2004) Novel azasterols as potential agents for treatment of leishmaniasis and trypanosomiasis. Antimicrobial Agents and Chemotherapy 48, 2937-2950CrossRefGoogle ScholarPubMed
161Gros, L. et al. (2006) Evaluation of azasterols as anti-parasitics. Journal of Medicinal Chemistry 49, 6094-6103CrossRefGoogle ScholarPubMed
162Gigante, F. et al. (2009) SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents. Bioorganic and Medicinal Chemistry 17, 5950-5961CrossRefGoogle ScholarPubMed
163Gros, L. et al. (2006) New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action. Antimicrobial Agents and Chemotherapy 50, 2595-2601CrossRefGoogle ScholarPubMed
164Cazzulo, J.J. et al. (1989) Further characterization and partial amino acid sequence of a cysteine proteinase from Trypanosoma cruzi. Molecular and Biochemical Parasitology 33, 33-41CrossRefGoogle ScholarPubMed
165Murta, A.C. et al. (1990) Structural and functional identification of GP57/51 antigen of Trypanosoma cruzi as a cysteine proteinase. Molecular and Biochemical Parasitology 43, 27-38CrossRefGoogle ScholarPubMed
166Eakin, A.E. et al. (1992) The sequence, organization, and expression of the major cysteine protease (cruzain) from Trypanosoma cruzi. Journal of Biological Chemistry 267, 7411-7420CrossRefGoogle ScholarPubMed
167Caffrey, C.R. et al. (2001) Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Molecular and Biochemical Parasitology 118, 61-73CrossRefGoogle ScholarPubMed
168Lima, A.P. et al. (1994) Identification of new cysteine protease gene isoforms in Trypanosoma cruzi. Molecular and Biochemical Parasitology 67, 333-338CrossRefGoogle ScholarPubMed
169Garcia, M.P. et al. (1998) Characterisation of a Trypanosoma cruzi acidic 30 kDa cysteine protease. Molecular and Biochemical Parasitology 91, 263-272CrossRefGoogle ScholarPubMed
170Nobrega, O.T. et al. (1998) Cloning and sequencing of tccb, a gene encoding a Trypanosoma cruzi cathepsin B-like protease. Molecular and Biochemical Parasitology 97, 235-240CrossRefGoogle ScholarPubMed
171Mackey, Z.B. et al. (2004) A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. Journal of Biological Chemistry 279, 48426-48433CrossRefGoogle ScholarPubMed
172Caffrey, C.R. and Steverding, D. (2009) Kinetoplastid papain-like cysteine peptidases. Molecular and Biochemical Parasitology 167, 12-19CrossRefGoogle ScholarPubMed
173McKerrow, J.H., McGrath, M.E. and Engel, J.C. (1995) The cysteine protease of Trypanosoma cruzi as a model for antiparasite drug design. Parasitology Today 11, 279-282CrossRefGoogle Scholar
174Engel, J.C. et al. (1998) Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection. Journal of Experimental Medicine 188, 725-734CrossRefGoogle ScholarPubMed
175Du, X. et al. (2000) Aryl ureas represent a new class of anti-trypanosomal agents. Chemistry and Biology 7, 733-742CrossRefGoogle ScholarPubMed
176Roush, W.R. et al. (2001) Potent second generation vinyl sulfonamide inhibitors of the trypanosomal cysteine protease cruzain. Bioorganic and Medicinal Chemistry Letters 11, 2759-2762CrossRefGoogle ScholarPubMed
177Du, X. et al. (2002) Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. Journal of Medicinal Chemistry 45, 2695-2707CrossRefGoogle ScholarPubMed
178Greenbaum, D.C. et al. (2004) Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi. Journal of Medicinal Chemistry 47, 3212-3219CrossRefGoogle ScholarPubMed
179Nkemgu, N.J. et al. (2003) Improved trypanocidal activities of cathepsin L inhibitors. International Journal of Antimicrobial Agents 22, 155-1559CrossRefGoogle ScholarPubMed
180Doyle, P.S. et al. (2007) A cysteine protease inhibitor cures Chagas' disease in an immunodeficient-mouse model of infection. Antimicrobial Agents and Chemotherapy 51, 3932-3939CrossRefGoogle Scholar
181Chen, Y.T. et al. (2008) Synthesis of macrocyclic trypanosomal cysteine protease inhibitors. Bioorganic and Medicinal Chemistry Letters 18, 5860-5863CrossRefGoogle ScholarPubMed
182Mallari, J.P. et al. (2008) Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB. Bioorganic and Medicinal Chemistry Letters 18, 2883-2885CrossRefGoogle ScholarPubMed
183Mallari, J.P. et al. (2008) Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. Journal of Medicinal Chemistry 51, 545-552CrossRefGoogle ScholarPubMed
184McGrath, M.E. et al. (1995) The crystal structure of cruzain: a therapeutic target for Chagas' disease. Journal of Molecular Biology 247, 251-259CrossRefGoogle ScholarPubMed
185Eakin, A.E. et al. (1993) Production of crystallizable cruzain, the major cysteine protease from Trypanosoma cruzi. Journal of Biological Chemistry 268, 6115-6118CrossRefGoogle ScholarPubMed
186Huang, L., Brinen, L.S. and Ellman, J.A. (2003) Crystal structures of reversible ketone-Based inhibitors of the cysteine protease cruzain. Bioorganic and Medicinal Chemistry 11, 21-29CrossRefGoogle ScholarPubMed
187Choe, Y. et al. (2005) Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Bioorganic and Medicinal Chemistry 13, 2141-2156CrossRefGoogle ScholarPubMed
188Kerr, I.D. et al. (2009) Vinyl sulfones as antiparasitic agents: A structural basis for drug design. Journal of Biological Chemistry 284, 25697-25703CrossRefGoogle ScholarPubMed
189Tomas, A.M., Miles, M.A. and Kelly, J.M. (1997) Overexpression of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, is associated with enhanced metacyclogenesis. European Journal of Biochemistry 244, 596-603CrossRefGoogle ScholarPubMed
190Abdulla, M.H. et al. (2008) RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. PLoS Neglected Tropical Diseases 2, e298CrossRefGoogle ScholarPubMed
191Krauth-Siegel, R.L. and Comini, M.A. (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochimica et Biophysica Acta 1780, 1236-1248CrossRefGoogle ScholarPubMed
192Krauth-Siegel, R.L. and Inhoff, O. (2003) Parasite-specific trypanothione reductase as a drug target molecule. Parasitology Research 90, S77-85CrossRefGoogle ScholarPubMed
193Jaeger, T. and Flohe, L. (2006) The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs. Biofactors 27, 109-120CrossRefGoogle ScholarPubMed
194Comini, M.A., Krauth-Siegel, R.L. and Flohe, L. (2007) Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes. Biochemical Journal 402, 43-49CrossRefGoogle ScholarPubMed
195Comini, M.A. et al. (2004) Valdiation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radical Biology and Medicine 36, 1289-1302CrossRefGoogle ScholarPubMed
196Ariyanayagam, M.R. et al. (2005) Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome. Biochemical Journal 391, 425-432CrossRefGoogle ScholarPubMed
197Wyllie, S. et al. (2009) Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods. Molecular Microbiology Jun 24; [Epub ahead of print]CrossRefGoogle ScholarPubMed
198Jockers-Scherubl, M.C., Schirmer, R.H. and Krauth-Siegel, R.L. (1989) Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds. European Journal of Biochemistry 180, 267-272CrossRefGoogle ScholarPubMed
199Fournet, A. et al. (1998) Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase. Journal of Enzyme Inhibition 13, 1-9CrossRefGoogle ScholarPubMed
200Zani, C.L. et al. (1997) Anti-plasmodial and anti-trypanosomal activity of synthetic naphtho[2,3-b]thiopen-4,9-quinones. Bioorganic and Medicinal Chemistry 5, 2185-2192CrossRefGoogle ScholarPubMed
201Bond, C.S. et al. (1999) Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors. Structure 7, 81-89CrossRefGoogle ScholarPubMed
202Gallwitz, H. et al. (1999) Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies. Journal of Medicinal Chemistry 42, 364-372CrossRefGoogle ScholarPubMed
203Fournet, A. et al. (2000) Efficacy of the bisbenzylisoquinoline alkaloids in acute and chronic Trypanosoma cruzi murine model. International Journal of Antimicrobial Agents 13, 189-195CrossRefGoogle ScholarPubMed
204Salmon-Chemin, L. et al. (2000) Parallel synthesis of a library of 1,4-naphthoquinones and automated screening of potential inhibitors of trypanothione reductase from Trypanosoma cruzi. Bioorganic and Medicinal Chemistry Letters 10, 631-635CrossRefGoogle Scholar
205Salmon-Chemin, L. et al. (2001) 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. Journal of Medicinal Chemistry 44, 548-565CrossRefGoogle Scholar
206Zani, C.L. and Fairlamb, A.H. (2003) 8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase. Memorias do Instituto Oswaldo Cruz 98, 565-568CrossRefGoogle ScholarPubMed
207Hamilton, C.J. et al. (2003) Ellman's-reagent-mediated regeneration of trypanothione in situ: substrate-economical microplate and time-dependent inhibition assays for trypanothione reductase. Biochemical Journal 369, 529-537CrossRefGoogle ScholarPubMed
208Hamilton, C.J. et al. (2003) Benzofuranyl 3,5-bis-polyamine derivatives as time-dependent inhibitors of trypanothione reductase. Bioorganic and Medicinal Chemistry 11, 3683-3693CrossRefGoogle ScholarPubMed
209Hamilton, C.J. et al. (2006) Time-dependent inhibitors of trypanothione reductase: analogues of the spermidine alkaloid lunarine and related natural products. Bioorganic and Medicinal Chemistry 14, 2266-2278CrossRefGoogle ScholarPubMed
210Stump, B. et al. (2007) Betraying the parasite's redox system: diaryl sulfide-based inhibitors of trypanothione reductase: subversive substrates and antitrypanosomal properties. ChemMedChem 2, 1708-1712CrossRefGoogle ScholarPubMed
211Martyn, D.C. et al. (2007) High-throughput screening affords novel and selective trypanothione reductase inhibitors with anti-trypanosomal activity. Bioorganic and Medicinal Chemistry Letters 17, 1280-1283CrossRefGoogle ScholarPubMed
212Czechowicz, J.A. et al. (2007) The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase. Journal of Organic Chemistry 72, 3689-3693CrossRefGoogle ScholarPubMed
213Stump, B. et al. (2009) Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. Chembiochem 10, 79-83CrossRefGoogle ScholarPubMed
214Stump, B. et al. (2008) Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities. Organic and Biomolecular Chemistry 6, 3935-3947CrossRefGoogle ScholarPubMed
215Holloway, G.A. et al. (2009) Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity. Antimicrobial Agents and Chemotherapy 53, 2824-2833CrossRefGoogle ScholarPubMed
216Holloway, G.A. et al. (2007) Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening. Bioorganic and Medicinal Chemistry Letters 17, 1422-1427CrossRefGoogle ScholarPubMed
217Cavalli, A. et al. (2009) Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase. Bioorganic and Medicinal Chemistry Letters 19, 3031-3035CrossRefGoogle ScholarPubMed
218Richardson, J.L. et al. (2009) Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. ChemMedChem 4, 1333-1340CrossRefGoogle ScholarPubMed
219Patterson, S. et al. (2009) Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase. ChemMedChem 4, 1341-1353CrossRefGoogle ScholarPubMed
220Zhang, Y. et al. (1993) Trypanosoma cruzi trypanothione reductase. Crystallization, unit cell dimensions and structure solution. Journal of Molecular Biology 232, 1217-1220CrossRefGoogle ScholarPubMed
221Lantwin, C.B. et al. (1994) The structure of Trypanosoma cruzi trypanothione reductase in the oxidized and NADPH reduced state. Proteins 18, 161-173CrossRefGoogle ScholarPubMed
222Jacoby, E.M. et al. (1996) Crystal structure of the Trypanosoma cruzi trypanothione reductase.mepacrine complex. Proteins 24, 73-803.0.CO;2-P>CrossRefGoogle ScholarPubMed
223Zhang, Y. et al. (1996) The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 A resolution. Protein Science 5, 52-61CrossRefGoogle ScholarPubMed
224Saravanamuthu, A. et al. (2004) Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design. Journal of Biological Chemistry 279, 29493-29500CrossRefGoogle ScholarPubMed
225Meiering, S. et al. (2005) Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. Journal of Medicinal Chemistry 48, 4793-4802CrossRefGoogle ScholarPubMed
226Ogungbe, I.V. and Setzer, W.N. (2009) Comparative molecular docking of antitrypanosomal natural products into multiple Trypanosoma brucei drug targets. Molecules 14, 1513-1536CrossRefGoogle ScholarPubMed
227Alphey, M.S. et al. (2003) Tryparedoxins from Crithidia fasciculata and Trypanosoma brucei: photoreduction of the redox disulfide using synchrotron radiation and evidence for a conformational switch implicated in function. Journal of Biological Chemistry 278, 25919-25925CrossRefGoogle ScholarPubMed
228Alphey, M.S., Konig, J. and Fairlamb, A.H. (2008) Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. Biochemical Journal 414, 375-381CrossRefGoogle ScholarPubMed
229Melchers, J. et al. (2008) Structural basis for a distinct catalytic mechanism in Trypanosoma brucei tryparedoxin peroxidase. Journal of Biological Chemistry 283, 30401-30411CrossRefGoogle ScholarPubMed
230Bitonti, A.J., Kelly, S.E. and McCann, P.P. (1984) Characterization of spermidine synthase from Trypanosoma brucei brucei. Molecular and Biochemical Parasitology 13, 21-28CrossRefGoogle ScholarPubMed
231Tekwani, B.L., Bacchi, C.J. and Pegg, A.E. (1992) Putrescine activated S-adenosylmethionine decarboxylase from Trypanosoma brucei brucei. Molecular and Cellular Biochemistry 117, 53-61CrossRefGoogle ScholarPubMed
232Yarlett, N. et al. (1993) S-adenosylmethionine synthetase in bloodstream Trypanosoma brucei. Biochimica et Biophysica Acta 1181, 68-76CrossRefGoogle ScholarPubMed
233Taylor, M.C. et al. (2008) Validation of spermidine synthase as a drug target in African trypanosomes. Biochemical Journal 409, 563-569CrossRefGoogle ScholarPubMed
234Huynh, T.T. et al. (2003) Gene knockdown of gamma-glutamylcysteine synthetase by RNAi in the parasitic protozoa Trypanosoma brucei demonstrates that it is an essential enzyme. Journal of Biological Chemistry 278, 39794-39800CrossRefGoogle ScholarPubMed
235Xiao, Y., McCloskey, D.E. and Phillips, M.A. (2009) RNA interference-mediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis. Eukaryotic Cell 8, 747-755CrossRefGoogle ScholarPubMed
236Tekwani, B.L. et al. (1992) Irreversible inhibition of S-adenosylmethionine decarboxylase of Trypanosoma brucei brucei by S-adenosylmethionine analogues. Biochemical Pharmacology 44, 905-911CrossRefGoogle ScholarPubMed
237Guo, J. et al. (1995) S-(5′-deoxy-5′-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cyclopentene (AdoMao): an irreversible inhibitor of S-adenosylmethionine decarboxylase with potent in vitro antitrypanosomal activity. Journal of Medicinal Chemistry 38, 1770-1777CrossRefGoogle ScholarPubMed
238Brun, R. et al. (1996) In vitro trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors. Antimicrobial Agents and Chemotherapy 40, 1442-1447CrossRefGoogle ScholarPubMed
239Marasco, C.J. Jr et al. , (2002) Synthesis and evaluation of analogues of 5′-([(Z)-4-amino-2-butenyl]methylamino)-5′-deoxyadenosine as inhibitors of tumor cell growth, trypanosomal growth, and HIV-1 infectivity. Journal of Medicinal Chemistry 45, 5112-5122CrossRefGoogle Scholar
240Hirth, B. et al. (2009) Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis (HAT). Bioorganic and Medicinal Chemistry Letters 19, 2916-2919CrossRefGoogle ScholarPubMed
241Bitonti, A.J. et al. (1990) Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase. Antimicrobial Agents and Chemotherapy 34, 1485-1490CrossRefGoogle ScholarPubMed
242Bacchi, C.J. et al. (1992) Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor. Antimicrobial Agents and Chemotherapy 36, 2736-2740CrossRefGoogle ScholarPubMed
243Bacchi, C.J. et al. (1996) In vivo trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors. Antimicrobial Agents and Chemotherapy 40, 1448-1453CrossRefGoogle ScholarPubMed
244Byers, T.L. et al. (1991) Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. Biochemical Journal 274, 527-533CrossRefGoogle ScholarPubMed
245Bacchi, C.J. et al. (2009) Trypanocidal activity of 8-methyl-5′-{[(Z)-4-aminobut-2-enyl]-(methylamino)}adenosine (Genz-644131), an adenosylmethionine decarboxylase inhibitor. Antimicrobial Agents and Chemotherapy 53, 3269-3272CrossRefGoogle Scholar
246Barker, R.H. Jr et al. (2009) Novel S-adenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis. Antimicrobial Agents and Chemotherapy 53, 2052-2058CrossRefGoogle ScholarPubMed
247Priotto, G. et al. (2007) Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Congo. Clinical Infectious Disease 45, 1435-1442CrossRefGoogle ScholarPubMed
248Rane, L., Rane, D. and Kinnamon, K.E. (1976) Screening large numbers of compounds in a model based on mortality of Trypanosoma rhodesiense infected mice. American Journal of Tropical Medicine and Hygiene 25, 395-400CrossRefGoogle Scholar
249Das, B.P. and Boykin, D.W. (1977) Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans. Journal of Medicinal Chemistry 20, 531-536CrossRefGoogle ScholarPubMed
250Ansede, J.H. et al. (2005) In vitro metabolism of an orally active O-methyl amidoxime prodrug for the treatment of CNS trypanosomiasis. Xenobiotica 35, 211-226CrossRefGoogle ScholarPubMed
251Conte, J.E. Jr et al. (1986) Use of a specific and sensitive assay to determine pentamidine pharmacokinetics in patients with AIDS. Journal of Infectious Diseases 154, 923-929CrossRefGoogle ScholarPubMed
252Burri, C. and Brun, R. (2003) Eflornithine for the treatment of human African trypanosomiasis. Parasitology Research 90, S49-52CrossRefGoogle ScholarPubMed
253Paulos, C. et al. (1989) Pharmacokinetics of a nitrofuran compound, nifurtimox, in healthy volunteers. International Journal of Clinical Pharmacology, Therapy and Toxicology 27, 454-457Google ScholarPubMed
254Raaflaub, J. and Ziegler, W.H. (1979) Single-dose pharmacokinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung 29, 1611-1614Google ScholarPubMed

Further reading, resources and contacts

The World Health Organization and The Centres for Disease Control and Prevention websites provide up-to-date information relating to trypanosomal diseases: