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2011, Number 2

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Rev Educ Bioquimica 2011; 30 (2)

Avances en la identificación de blancos terapéuticos y el diseño racional de fármacos contra la enfermedad de chagas

García-Torres I, Pérez-Montfort R

Language: Spanish
References: 43
Page: 68-81
PDF size: 680.68 Kb.


ABSTRACT

Chagas disease affects over 10 million people around the world, and it is considered one of the most neglected tropical diseases. Even though this disease was discovered more than 100 years ago, there is not an effective drug against Chagas in any of its two main stages. There are several studies around the world focused on the selection of potential targets for drug development against Chagas disease. In this work, we made a revision of these attempts with emphasis in those works based on the metabolic differences between Trypanosoma cruzi (the etiological agent of chagas disease) and its mammalian host. As a result of the detailed analysis of these metabolic differences, a great number of potential targets for rational drug design have been revealed, and some of the most promising molecules designed are now being tested in early preclinical studies.


REFERENCES

  1. Aufderheide AC, W Salo M, Madden J, Streitz J, Buikstra F, Guhl B, Arriaza C, Renier L, E Wittmers, Jr., G Fornaciari, M Allison (2004) A 9000-year record of Chagas’ disease. Proc Natl Acad Sci USA 101:2034–2039.

  2. Bernstein RE (1984) Darwin’s illness: Chagas’ disease resurgens. J R Soc Med 77(7): 608-609.

  3. Wilkinson SR, Kelly JM.(2009) Trypanocidal drugs: mechanisms, resistance and new targets. Expert Rev Mol Med 11:e31.

  4. Maya J, Cassels B, Iturriaga-Vasquez P, . Ferreira J, Faúndez M, Galanti N, Ferreira A, Morello A (2006) Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp Biochem Physiol A Mol Integr Physiol 146:601–620.

  5. Faundez M, Pino L, Letelier P, Ortiz C, López R, Seguel C, Ferreira J, Pavani M, Morello A, Maya JD (2005) Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrob Agents Chemother 49:126–130.

  6. Apt W (2010) Current and developing therapeutic agents in the treatment of Chagas disease. Drug Design, Development and Therapy 4:243-253.

  7. Murta SM, Krieger MA, Montenegro LR, Campos FF, Probst CM, Avila AR, Muto NH, de Oliveira RC, Nunes LR, Nirdé P, Bruna-Romero O, Goldenberg S, Romanha AJ (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. Mol Biochem Parasitol 146, 151-162.

  8. de Souza W (2002). Special organelles of some pathogenic protozoa. Parasitol Res 88:1013-1025.

  9. Tielens AG, van Hellemond JJ (2009) Surprising variety in energy metabolism within Trypanosomatidae. Trends Parasitol 25:482-90.

  10. Chauhan SC, Padmanabhan PK, Madhubala R (2008) Glyoxalase pathway of trypanosomatid parasites: a promising chemotherapeutic target. Curr Drug Targets 9:957-965.

  11. Jose Cazzulo J, Stoka V, Turk V (2001) The major cysteine proteinase of Trypanosoma cruzi: a valid target for chemotherapy of Chagas disease. Curr Pharm Des 7:1143-1156

  12. Urbina JA (2009) Ergosterol biosynthesis and drug development for Chagas disease.Mem Inst Oswaldo Cruz 104 Suppl 1:311-318.

  13. Naula C, Parsons M, Mottram JC (2005) Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta 1754:151-159.

  14. Sanz-Rodríguez CE, Concepción JL, Pekerar S, Oldfield E, Urbina JA (2007).Bisphosphonates as inhibitors of Trypanosoma cruzi hexokinase: kinetic and metabolic studies. J Biol Chem 282:12377-12387.

  15. Olivares-Illana V, Pérez-Montfort R, López- Calahorra F, Costas M, Rodríguez-Romero A, Tuena de Gómez-Puyou M, Gómez Puyou A (2006) Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor. Biochemistry 45:2556-2560.

  16. Olivares-Illana V, Rodríguez-Romero A, Becker I, Berzunza M, García J, Pérez-Montfort R, Cabrera N, López-Calahorra F, de Gómez-Puyou MT, Gómez-Puyou A (2007) Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi. PLoS Negl Trop Dis 1(1): e01. doi:10.1371/journal.pntd.0000001.

  17. Alvarez G, Aguirre-López B, Varela J, Cabrera M, Merlino A, López GV, Lavaggi ML, Porcal W, Di Maio R, González M, Cerecetto H, Cabrera N, Pérez-Montfort R, de Gómez-Puyou MT, Gómez-Puyou A (2010). Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interfaceirreversible inhibitors with anti-trypanosomal activity. Eur J Med Chem 45:5767-5772.

  18. Aronov AM, Suresh S, Buckner FS, Van Voorhis WC, Verlinde CL, Opperdoes FR, Hol WG, Gelb MH (1999) Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U.S.A. 96:4273-4278.

  19. Silva JJ, Guedes PM, Zottis A, Balliano TL, Nascimento Silva FO, França Lopes LG, Ellena J, Oliva G, Andricopulo AD, Franco DW, Silva JS (2010) Novel ruthenium complexes as potential drugs for Chagas’s disease: enzyme inhibition and in vitro/in vivo trypanocidal activity. Br J Pharmacol 160:260-269.

  20. Acosta H, Dubourdieu M, Quiñones W, Cáceres A, Bringaud F, Concepción JL (2004) Pyruvate phosphate dikinase and pyrophosphate metabolism in the glycosome of Trypanosoma cruzi epimastigotes.Comp Biochem Physiol B Biochem Mol Biol 138:347-356.

  21. Smith K, Nadeau K, Bradley M, Walsh C, Fairlamb AH (1992) Purification of glutathionylspermidine and trypanothione synthetases from Crithidia fasciculata. Protein Sci 1:874-883.

  22. Oza SL, Tetaud E, Ariyanayagam MR, Warnon SS, Fairlamb AH (2002) A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi. J Biol Chem 277:35853-35861.

  23. Ariyanayagam MR, Oza SL, Mehlert A, Fairlamb AH (2003) Bis(glutathionyl)spermine and other novel trypanothione analogues in Trypanosoma cruzi. J Biol Chem 278:27612-27619.

  24. Perez-Pineiro R, Burgos A, Jones DC, Andrew LC, Rodriguez H, Suarez M, Fairlamb AH, Wishart DS (2009)Development of a novel virtual screening cascade protocol to identify potential trypanothione reductase inhibitors. J Med Chem 52:1670-1680.

  25. Irsch T, Krauth-Siegel RL (2004) Glyoxalase II of African trypanosomes is trypanothionedependent. J. Biol. Chem 279:22209–22217.

  26. Vickers TJ, Greig N, Fairlamb AH (2004) A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Proc Natl Acad Sci U.S.A. 101:13186–13191.

  27. Greig N, Wyllie S, Vickers TJ, Fairlamb AH (2006)Trypanothione-dependent glyoxalase I in Trypanosoma cruzi. Biochem J. 400:217-223.

  28. McKerrow JH, Doyle PS, Engel JC, Podust LM, Robertson SA, Ferreira R, Saxton T, Arkin M, Kerr ID, Brinen LS, Craik CS (2009) Two approaches to discovering and developing new drugs for Chagas disease. Mem Inst Oswaldo Cruz. 104 Suppl 1:263-269.

  29. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong le T, Falgueyret JP, Kimmel DB, Lamontagne S, Léger S, LeRiche T, Li CS, Massé F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Thérien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC (2008) The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 18:923-928.

  30. Beaulieu C, Isabel E, Fortier A, Massé F, Mellon C, Méthot N, Ndao M, Nicoll-Griffith D, Lee D, Park H, Black WC (2010) Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease. Bioorg Med Chem Lett 20:7444-7449.

  31. Urbina JA (2002) Chemotherapy of Chagas disease. Curr Pharm Des 8:287-95.

  32. Urbina JA, Docampo R (2003) Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol 19:495-501.

  33. Silva DT, de Nazareth S L de Meirelles M, Almeida D, Urbina JA, Pereira MC (2006) Cytoskeleton reassembly in cardiomyocytes infected by Trypanosoma cruzi is triggered by treatment with ergosterol biosynthesis inhibitors. Int J Antimicrob Agents 27:530-537.

  34. Urbina JA, Payares G, Sanoja C, Molina J, Lira R, Brener Z, Romanha AJ (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. Int J Antimicrob Agents 21:39-48.

  35. Chen CK, Doyle PS, Yermalitskaya LV, Mackey ZB, Ang KK, McKerrow JH, Podust LM (2009). Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. PLoS Negl Trop Dis 3(2):e372.

  36. Chen CK, Leung SS, Guilbert C, Jacobson MP, McKerrow JH, Podust LM (2010) Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole. PLoS Negl Trop Dis 4:e651.

  37. Urbina JA, Concepcion JL, Caldera A, Payares G, Sanoja C, Otomo T, Hiyoshi H. (2004). In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 48:2379-2387.

  38. Sealey-Cardona M, Cammerer S, Jones S, Ruiz-Pérez LM, Brun R, Gilbert IH, Urbina JA, González-Pacanowska D (2007) Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives.Antimicrob Agents Chemother 51:2123-2129.

  39. Urbina JA, Concepcion JL, Montalvetti A, Rodriguez JB, Docampo R (2003) Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas’ disease. Antimicrob Agents Chemother 47:2047-50.

  40. Gerpe A, Odreman-Nuñez I, Draper P, Boiani L, Urbina JA, González M, Cerecetto H (2007) Heteroallyl-containing 5-nitrofuranes as new anti-Trypanosoma cruzi agents with a dual mechanism of action. Bioorg Med Chem 16:569-577.

  41. Gerpe A, Alvarez G, Benítez D, Boiani L, Quiroga M, Hernández P, Sortino M, Zacchino S, González M, Cerecetto H (2009) 5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene. Bioorg Med Chem 17:7500-7509.

  42. Gómez EB, Santori MI, Laría S, Engel JC, Swindle J, Eisen H, Szankasi P, Téllez-Iñón MT (2001) Characterization of the Trypanosoma cruzi Cdc2p-related protein kinase 1 and identification of three novel associating cyclins. Mol Biochem Parasitol 113:97-108.

  43. Knockaert M, Gray N, Damiens E, Chang YT, Grellier P, Grant K, Fergusson D, Mottram J, Soete M, Dubremetz JF, Le Roch K, Doerig C, Schultz P, Meijer L (2000) Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors. Chem Biol 7:411-422.




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