In Search of Trypanocidal Drugs

Antiparasitic and Antibacterial Drug Discovery: From Molecular Targets to Drug Candidates

Volumn , Issue , 2009, Pages 211-226

  Flohé, Leopold ^a  

^a Molisa GmbH   (Germany)

Author keywords

Drug targets; Leishmaniasis; Paullone; Trypanosomiasis; Trypanothione; Trypanothione reductase; Trypanothione synthetase; Tryparedoxin; Tryparedoxin peroxidase

Indexed keywords

EID: 84890979454     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527626816.ch12     Document Type: Chapter

References (87)

1. d'Ieteren, G. and Kimani, K. (2008) Indigenous genetic resources: A sustainable and environmentally friendly option for livestock production in areas at risk from trypanosomes. www.scienceinafrica.co.za/Ndama.
2. Bunkley-Williams, L., Williams, J. and Ernest, E.H. (2006) New records of parasites for culture Cobia, Rachycentron canadium (Perciformes: Rachycentridae) in Puerto Rico. Revista de Biologia Tropical, 44, 1-7.
3. Croft, S.L., Barrett, M.P. and Urbina, J.A. (2005) Chemotherapy of trypanosomiases and leishmaniasis. Trends in Parasitology, 21, 508-512.
4. Fairlamb, A.H. and Cerami, A. (1992) Metabolism and functions of trypanothione in the Kinetoplastida. Annual Review of Microbiology, 46, 695-729.
5. Flohe, L. (1998) The Achilles' heel of trypanosomatids: trypanothione-mediated hydroperoxide metabolism. Biofactors (Oxford, England), 8, 87-91.
6. Flohe, L., Hecht, H.J. and Steinert, P. (1999) Glutathione and trypanothione in parasitic hydroperoxide metabolism. Free Radical Biology & Medicine, 27, 966-984.
7. Krauth-Siegel, L.R., Comini, M.A. and Schlecker, T. (2007) The Trypanothione System, in Subcellular Biochemistry, vol. 44, Peroxiredoxin Systems (eds L. Flohe and J.R. Harris), Springer, New York, pp. 231-251.
8. Krauth-Siegel, R.L., Bauer, H. and Schirmer, R.H. (2005) Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Angewandte Chemie (International Edition in English), 44, 690-715.
9. Krauth-Siegel, R.L., Meiering, S.K. and Schmidt, H. (2003) The parasite-specific trypanothione metabolism of trypanosoma and leishmania. Biological Chemistry, 384, 539-549.
10. Ondarza, R.N. (2007) Drug targets from human pathogenic amoebas: Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri. Infectious Disorders-Drug Targets, 7, 266-280.
11. Fairlamb, A.H. and Cerami, A. (1985) Identification of a novel, thiol-containing co-factor essential for glutathione reductase enzyme activity in trypanosomatids. Molecular and Biochemical Parasitology, 14, 187-198.
12. Fairlamb, A.H., Blackburn, P., Ulrich, P., Chait, B.T. and Cerami, A. (1985) Trypanothione: a novel bis(glutathionyl) spermidine cofactor for glutathione reductase in trypanosomatids. Science, 227, 1485-1487.
13. Schmidt, H. and Krauth-Siegel, R.L. (2003) Functional and physicochemical characterization of the thioredoxin system in Trypanosoma brucei. The Journal of Biological Chemistry, 278, 46329-46336.
14. Nogoceke, E., Gommel, D.U., Kiess, M., Kalisz, H.M. and Flohe, L. (1997) Aunique cascade of oxidoreductases catalyses trypanothione-mediated peroxide metabolism in Crithidia fasciculata. Biological Chemistry Hoppe-Seyler, 378, 827-836.
15. Krauth-Siegel, R.L., Comini, A.M. and Schlecker, T. (2007) The trypanothione system, in Peroxiredoxin Systems: Structure and Function (eds L. Flohe and J.R. Harris), Springer, New York, pp. 231-251.
16. Dormeyer, M., Reckenfelderbaumer, N., Ludemann, H. and Krauth-Siegel, R.L. (2001) Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase. The Journal of Biological Chemistry, 276, 10602-10606.
17. Comini, M.A., Guerrero, S.A., Haile, S., Menge, U., Lunsdorf, H. and Flohe, L. (2004) Valdiation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radical Biology & Medicine, 36, 1289-1302.
18. Castro, H., Sousa, C., Novais, M., Santos, M., Budde, H., Cordeiro-da-Silva, A., Flohe, L. and Tomas, A.M. (2004) Two linked genes of Leishmania infantum encode tryparedoxins localised to cytosol and mitochondrion. Molecular and Biochemical Parasitology, 136, 137-147.
19. Castro, H., Sousa, C., Santos, M., Cordeiro-da-Silva, A., Flohe, L. and Tomas, A.M. (2002) Complementary antioxidant defense by cytoplasmic and mitochondrial peroxiredoxins in Leishmania infantum. Free Radical Biology & Medicine, 33, 1552-1562.
20. Wilkinson, S.R., Temperton, N.J., Mondragon, A. and Kelly, J.M. (2000) Distinct mitochondrial and cytosolic enzymes mediate trypanothione-dependent peroxide metabolism in Trypanosoma cruzi. The Journal of Biological Chemistry, 275, 8220-8225.
21. Budde, H., Flohe, L., Hecht, H.J., Hofmann, B., Stehr, M., Wissing, J. and Lunsdorf, H. (2003) Kinetics and redox-sensitive oligomerisation reveal negative subunit cooperativity in tryparedoxin peroxidase of Trypanosoma brucei brucei. Biological Chemistry Hoppe-Seyler, 384, 619-633.
22. Castro, H., Budde, H., Flohe, L., Hofmann, B., Lunsdorf, H., Wissing, J. and Tomas, A.M. (2002) Specificity and kinetics of a mitochondrial peroxiredoxin of Leishmania infantum. Free Radical Biology & Medicine, 33, 1563-1574.
23. Thomson, L., Denicola, A. and Radi, R. (2003) The trypanothione-thiol system in Trypanosoma cruzi as a key antioxidant mechanism against peroxynitrite-mediated cytotoxicity. Archives of Biochemistry and Biophysics, 412, 55-64.
24. Trujillo, M., Budde, H., Pineyro, M.D., Stehr, M., Robello, C., Flohe, L. and Radi, R. (2004) Trypanosoma brucei and Trypanosoma cruzi tryparedoxin peroxidases catalytically detoxify peroxynitrite via oxidation of fast reacting thiols. The Journal of Biological Chemistry, 279, 34175-34182.
25. Trujillo, M., Ferrer-Sueta, G., Thomson, L., Flohe, L. and Radi, R. (2007) Kinetics of peroxiredoxins and their role in the decomposition of peroxynitrite, in Peroxyredoxin Systems, vol. 44, Subcellular Biochemistry (eds L. Flohe and J.R. Harris), Springer, New York, pp. 83-113.
26. Schlecker, T., Schmidt, A., Dirdjaja, N., Voncken, F., Clayton, C. and Krauth-Siegel, R.L. (2005) Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei. The Journal of Biological Chemistry, 280, 14385-14394.
27. Wilkinson, S.R., Obado, S.O., Mauricio, I.L. and Kelly, J.M. (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, 13453-13458.
28. Krauth-Siegel, R.L. and Inhoff, O. (2003) Parasite-specific trypanothione reductase as a drug target molecule. Parasitology Research, 90 (Suppl. 2), S77-S85.
29. Irsch, T. and Krauth-Siegel, R.L. (2004) Glyoxalase II of African trypanosomes is trypanothione-dependent. The Journal of Biological Chemistry, 279, 22209-22217.
30. Sousa Silva, M., Ferreira, A.E., Tomas, A.M., Cordeiro, C. and Ponces Freire, A. (2005) Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation. FEBS Journal, 272, 2388-2398.
31. Vickers, T.J., Greig, N. and Fairlamb, A.H. (2004) A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Proceedings of the National Academy of Sciences of the United States of America, 101, 13186-13191.
32. Vickers, T.J. and Fairlamb, A.H. (2004) Trypanothione S-transferase activity in a trypanosomatid ribosomal elongation factor 1B. The Journal of Biological Chemistry, 279, 27246-27256.
33. Vickers, T.J., Wyllie, S. and Fairlamb, A.H. (2004) Leishmania major elongation factor 1B complex has trypanothione S-transferase and peroxidase activity. The Journal of Biological Chemistry, 279, 49003-49009.
34. Onn, I., Milman-Shtepel, N. and Shlomai, J. (2004) Redox potential regulates binding of universal minicircle sequence binding protein at the kinetoplast DNA replication origin. Eukaryotic Cell, 3, 277-287.
35. Comini, M., Menge, U. and Flohe, L. (2003) Biosynthesis of trypanothione in Trypanosoma brucei brucei. Biological Chemistry Hoppe-Seyler, 384, 653-656.
36. Comini, M., Menge, U., Wissing, J. and Flohe, L. (2005) Trypanothione synthesis in crithidia revisited. The Journal of Biological Chemistry, 280, 6850-6860.
37. Koenig, K., Menge, U., Kiess, M., Wray, V. and Flohe, L. (1997) Convenient isolation and kinetic mechanism of glutathionylspermidine synthetase from Crithidia fasciculata. The Journal of Biological Chemistry, 272, 11908-11915.
38. Oza, S.L., Ariyanayagam, M.R., Aitcheson, N. and Fairlamb, A.H. (2003) Properties of trypanothione synthetase from Trypanosoma brucei. Molecular and Biochemical Parasitology, 131, 25-33.
39. Oza, S.L., Ariyanayagam, M.R. and Fairlamb, A.H. (2002) Characterization of recombinant glutathionylspermidine synthetase/amidase from Crithidia fasciculata. The Biochemical Journal, 364, 679-686.
40. Oza, S.L., Shaw, M.P., Wyllie, S. and Fairlamb, A.H. (2005) Trypanothione biosynthesis in Leishmania major. Molecular and Biochemical Parasitology, 139, 107-116.
41. Oza, S.L., Tetaud, E., Ariyanayagam, M.R., Warnon, S.S. and Fairlamb, A.H. (2002) A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi. The Journal of Biological Chemistry, 277, 35853-35861.
42. Fairlamb, A.H., Henderson, G.B., Bacchi, C.J. and Cerami, A. (1987) In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in blood stream forms of Trypanosoma brucei. Molecular and Biochemical Parasitology, 24, 185-191.
43. Fairlamb, 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, 2607-2611.
44. Paulinoa, M., Iribarnea, F., Dubinb, M., Aguilera-Moralesc, S., Tapiad, O. and Stoppani, A.O. (2005) The chemotherapy of Chagas' disease: an overview. Mini-Reviews in Medicinal Chemistry, 5, 499-519.
45. Henschler, D. (1996) Antiprotozoenmittel, in Allgemeine und Spezielle Pharmakologie und Toxikologie, 7th edn (eds W. Forth, D. Henschler, W. Rummel and K. Starke), Spektrum Acad. Verlag, Heidelberg, pp. 762-772.
46. Kelly, J.M., Taylor, M.C., Smith, K., Hunter, K.J. and Fairlamb, A.H. (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, 29-37.
47. Krieger, S., Schwarz, W., Ariyanayagam, M.R., Fairlamb, A.H., Krauth-Siegel, R.L. and Clayton, C. (2000) Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Molecular Microbiology, 35, 542-552.
48. Tovar, J., Cunningham, M.L., Smith, A.C., Croft, S.L. and Fairlamb, A.H. (1998) Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival. Proceedings of the National Academy of Sciences of the United States of America, 95, 5311-5316.
49. Ariyanayagam, M.R., Oza, S.L., Guther, M.L. and Fairlamb, A.H. (2005) Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome. The Biochemical Journal, 391, 425-432.
50. Comini, M.A., Krauth-Siegel, R.L. and Flohe, L. (2007) Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes. The Biochemical Journal, 402, 43-49.
51. Wilkinson, S.R., Horn, D., Prathalingam, S.R. and Kelly, J.M. (2003) RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the african trypanosome. The Journal of Biological Chemistry, 278, 31640-31646.
52. Schmidt, A., Clayton, C.E. and Krauth-Siegel, R.L. (2002) Silencing of the thioredoxin gene in Trypanosoma brucei brucei. Molecular and Biochemical Parasitology, 125, 207-210.
53. Piacenza, L., Peluffo, G., Alvarez, M.N., Kelly, J.M., Wilkinson, S.R. and Radi, R., (2008) Peroxiredoxins play a major role in protecting Trypanosoma cruzi against macrophage-and endogenously-derived peroxynitrite. The Biochemical Journal, 410, 359-368.
54. Lin, Y.C., Hsu, J.Y., Chiang, S.C. and Lee, S.T. (2005) Distinct overexpression of cytosolic and mitochondrial tryparedoxin peroxidases results in preferential detoxification of different oxidants in arsenite-resistant Leishmania amazonensis with and without DNA amplification. Molecular and Biochemical Parasitology, 142, 66-75.
55. Castro, H. (2006) Hydroperoxide metabolism in Leishmania infantum. Ph. D. Thesis Institute for Molecular and Cell Biology. Universidade do Porto, Porto, Portugal, pp. 1-140.
56. Wilkinson, S.R., Meyer, D.J., Taylor, M.C., Bromley, E.V., Miles, M.A. and Kelly, J.M. (2002) The Trypanosoma cruzi enzyme TcGPXI is a glycosomal peroxidase and can be linked to trypanothione reduction by glutathione or tryparedoxin. The Journal of Biological Chemistry, 277, 17062-17071.
57. Ludemann, H., Dormeyer, M., Sticherling, C., Stallmann, D., Follmann, H. and Krauth-Siegel, R.L. (1998) Trypanosoma brucei tryparedoxin, a thioredoxin-like protein in African trypanosomes. FEBS Letters, 431, 381-385.
58. Ullu, E., Tschudi, C. and Chakraborty, T. (2004) RNA interference in protozoan parasites. Cellular Microbiology, 6, 509-519.
59. Keller, T.H., Pichota, A. and Yin, Z. (2006) A practical view of "druggability". Current Opinion in Chemical Biology, 10, 357-361.
60. Steinert, P., Plank-Schumacher, K., Montemartini, M., Hecht, H.J. and Flohe, L. (2000) Permutation of the active site motif of tryparedoxin 2. Biological Chemistry, 381, 211-219.
61. Krumme, D., Budde, H., Hecht, H.J., Menge, U., Ohlenschlager, O., Ross, A., Wissing, J. et al. (2003) NMR studies of the interaction of tryparedoxin with redox-inactive substrate homologues. Biochemistry, 42, 14720-14728.
62. Hofmann, B., Budde, H., Bruns, K., Guerrero, S.A., Kalisz, H.M., Menge, U., Montemartini, M. et al. (2001) Structures oftryparedoxins revealing interaction with trypanothione. Biological Chemistry, 382, 459-471.
63. Hofmann, B., Hecht, H.J. and Flohe, L. (2002) Peroxiredoxins. Biological Chemistry Hoppe-Seyler, 383, 347-364.
64. Schlecker, T., Comini, M.A., Melchers, J., Ruppert, T. and Krauth-Siegel, R.L. (2007) Catalytic mechanism of the glutathione peroxidase-type tryparedoxin peroxidase of Trypanosoma brucei. The Biochemical Journal, 405, 445-454.
65. Budde, H., Flohe, L., Hofmann, B. and Nimtz, M. (2003) Verification of the interaction of a tryparedoxin peroxidase with tryparedoxin by ESI-MS/MS. Biological Chemistry Hoppe-Seyler, 384, 1305-1309.
66. Kuriyan, J., Kong, X.P., Krishna, T.S., Sweet, R.M., Murgolo, N.J., Field, H., Cerami, A. and Henderson, G.B. (1991) X-ray structure oftrypanothione reductase from Crithidia fasciculata at 2.4-A resolution. Proceedings of the National Academy of Sciences of the United States of America, 88, 8764-8768.
67. Hunter, W.N., Bailey, S., Habash, J., Harrop, S.J., Helliwell, J.R., Aboagye-Kwarteng, T., Smith, K. and Fairlamb, A.H. (1992) Active site of trypanothione reductase. A target for rational drug design. Journal of Molecular Biology, 227, 322-333.
68. Lantwin, C.B., Schlichting, I., Kabsch, W., Pai, E.F. and Krauth-Siegel, R.L. (1994) The structure of Trypanosoma cruzi trypanothione reductase in the oxidized and NADPH reduced state. Proteins, 18, 161-173.
69. Jacoby, E.M., Schlichting, I., Lantwin, C.B., Kabsch, W. and Krauth-Siegel, R.L. (1996) Crystal structure of the Trypanosoma cruzi trypanothione reductase.mepacrine complex. Proteins, 24, 73-80.
70. Bonse, S., Richards, J.M., Ross, S.A., Lowe, G. and Krauth-Siegel, R.L. (2000) (2, 2':6', 2"-Terpyridine)platinum(II) complexes are irreversible inhibitors of Trypanosoma cruzi trypanothione reductase but not of human glutathione reductase. Journal of Medicinal Chemistry, 43, 4812-4821.
71. Inhoff, O., Richards, J.M., Briet, J.W., Lowe, G. and Krauth-Siegel, R.L. (2002) Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. Journal of Medicinal Chemistry, 45, 4524-4530.
72. Lee, B., Bauer, H., Melchers, J., Ruppert, T., Rattray, L., Yardley, V., Davioud-Charvet, E. and Krauth-Siegel, R.L. (2005) Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. Journal of Medicinal Chemistry, 48, 7400-7410.
73. Meiering, S., Inhoff, O., Mies, J., Vincek, A., Garcia, G., Kramer, B., Dormeyer, M. and Krauth-Siegel, R.L. (2005) Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. Journal of Medicinal Chemistry, 48, 4793-4802.
74. Otero, L., Vieites, M., Boiani, L., Denicola, A., Rigol, C., Opazo, L., Olea-Azar, C. et al. (2006) Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets. Journal of Medicinal Chemistry, 49, 3322-3331.
75. Fyfe, P.K., Oza, S.L., Fairlamb, A.H. and Hunter, W.N. (2008) Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities. Journal of Biological Chemistry, 283, 17672-17680.
76. Pai, C.H., Chiang, B.Y., Ko, T.P., Chou, C.C., Chong, C.M., Yen, F.J., Chen, S. et al. (2006) Dual binding sites for translocation catalysis by Escherichia coli glutathionylspermidine synthetase. EMBO Journal, 25, 5970-5982.
77. Granot, Y. (2002) The ATP site of protein kinases as target for drug development: from natural compounds to gleevec. The Israel Medical Association Journal, 4, 633-635.
78. Stuhlmann, F., Flohe, L., Schinzer, D. and Jaeger, T. (2005) N-substituted 2-(6-oxo-6, 7-dihydro-5H-benzo[2, 3] azepino[4, 5-b]indol-5-yl)-acetamides for treating tropical diseases. EP 05 018 385.4.
79. Zaharevitz, D.W., Gussio, R., Leost, M., Senderowicz, A.M., Lahusen, T., Kunick, C., Meijer, L. and Sausville, E.A. (1999) Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Research, 59, 2566-2569.
80. Knockaert, M., Wieking, K., Schmitt, S., Leost, M., Grant, K.M., Mottram, J.C., Kunick, C. and Meijer, L. (2002) Intracellular Targets of Paullones. Identification following affinity purification on immobilized inhibitor. The Journal of Biological Chemistry, 277, 25493-25501.
81. Pies, T. (2003) 9-Substitued Paullones: Synthesis and Structure-Activity Relationships. Thesis, Dept. Pharmaceutical Chemistry, University of Hamburg, Hamburg, Germany, pp. 1-325.
82. Schultz, C., Link, A., Leost, M., Zaharevitz, D.W., Gussio, R., Sausville, E.A., Meijer, L. and Kunick, C. (1999) Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity. Journal of Medicinal Chemistry, 42, 2909-2919.
83. Reichwald, C., Shimony, O., Dunkel, U., Sacerdoti-Sierra, N., Jaffe, C.L. and Kunick, C. (2008) 2-(3-Aryl-3-oxopropen-1-yl)-9-tert-butyl-paullones: A New Antileishmanial Chemotype. Journal of Medicinal Chemistry, 51, 659-665.
84. Ravaschino, E.L., Docampo, R. and Rodriguez, J.B. (2006) Design synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis. Journal of Medicinal Chemistry, 49, 426-435.
85. Salmon-Chemin, L., Buisine, E., Yardley, V., Kohler, S., Debreu, M.A., Landry, V., Sergheraert, C. 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, 548-565.
86. Daunes, S., D'Silva, C., Kendrick, H., Yardley, V. and Croft, S.L. (2001) QSAR study on the contribution oflog P and E(s) to the in vitro antiprotozoal activity of glutathione derivatives. Journal of Medicinal Chemistry, 44, 2976-2983.
87. Babior, B.M. (2000) Phagocytes and oxidative stress. The American Journal of Medicine, 109, 33-44.