The Expected Outcome of the Trypanosoma cruzi Proteomic Map: A Review of Its Potential Biological Applications for Drug Target Discovery

  • Rubem F. S. Menna-Barreto
  • Jonas Perales
Part of the Subcellular Biochemistry book series (SCBI, volume 74)


Chagas disease is a neglected tropical illness endemic to Latin America, and its treatment remains unsatisfactory. This disease is caused by the hemoflagellate protozoan Trypanosoma cruzi, which has a complex life cycle involving three evolutive forms in both vertebrate and invertebrate hosts. Targeting metabolic pathways in the parasite for rational drug design represents a promising research field. This research area requires high performance techniques and proteomics become a powerful tool in this context. Here, we review advances in the construction of proteomic maps of the different forms of T. cruzi, emphasizing their biological applications towards the identification of alternative candidates for drug intervention.


Arginine Kinase Tyrosine Aminotransferase Trypanocidal Activity Serine Carboxypeptidase Heat Shock Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Two-dimensional electrophoresis




Liquid chromatography and tandem mass spectrometry


Matrix-assisted laser desorption/ionization-time of flight


Platelet-activating factor


  1. Abad-Franch F, Santos WS, Schofield CJ (2010) Research needs for Chagas disease prevention. Acta Trop 115:44–54PubMedCrossRefGoogle Scholar
  2. Andrade HM, Murta SM, Chapeaurouge A et al (2008) Proteomic analysis of Trypanosoma cruzi resistance to Benznidazole. J Proteome Res 7:2357–2367PubMedCrossRefGoogle Scholar
  3. Atwood JA 3rd, Weatherly DB, Minning TA et al (2005) The Trypanosoma cruzi proteome. Science 309:473–476PubMedCrossRefGoogle Scholar
  4. Atwood JA 3rd, Minning T, Ludolf F et al (2006) Glycoproteomics of Trypanosoma cruzi trypomastigotes using subcellular fractionation, lectin affinity, and stable isotope labeling. J Proteome Res 5:3376–3384PubMedCrossRefGoogle Scholar
  5. Batista DG, Pacheco MG, Kumar A et al (2010) Biological, ultrastructural effect and subcellular localization of aromatic diamidines in Trypanosoma cruzi. Parasitology 137:251–259PubMedCrossRefGoogle Scholar
  6. Beghini DG, Ferreira ATS, Caminha MA et al (2012) New insights in Trypanosoma cruzi proteomic map: further post-translational modifications and potential drug targets in Y strain epimastigotes. J Integr Omics 2:106–113Google Scholar
  7. Buckner FS, Navabi N (2010) Advances in Chagas disease drug development. Curr Opin Infect Dis 23:609–616, 2009–2010PubMedCrossRefGoogle Scholar
  8. Cazzulo JJ (1994) Intermediate metabolism in Trypanosoma cruzi. J Bioenerg Biomembr 26:157–165PubMedCrossRefGoogle Scholar
  9. Clayton C, Shapira M (2007) Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Mol Biochem Parasitol 156:93–101PubMedCrossRefGoogle Scholar
  10. Cordero EM, Nakayasu ES, Gentil LG et al (2009) Proteomic analysis of detergent-solubilized membrane proteins from insect-developmental forms of Trypanosoma cruzi. J Proteome Res 8:3642–3652PubMedCrossRefGoogle Scholar
  11. Dantas AP, Barbosa HS, de Castro SL (2003) Biological and Ultrastructural effects of the anti-microtubule agent taxol against Trypanosoma cruzi. J Submicrosc Cytol Pathol 35:287–294PubMedGoogle Scholar
  12. Dantas AP, Salomão K, Barbosa HS et al (2006) The effect of Bulgarian propolis against Trypanosoma cruzi and during its interaction with host cells. Mem Inst Oswaldo Cruz 101:207–211PubMedCrossRefGoogle Scholar
  13. de Godoy LM, Marchini FK, Pavoni D et al (2012) Quantitative proteomics of Trypanosoma cruzi during metacyclogenesis. Proteomics 12:2694–2703PubMedCrossRefGoogle Scholar
  14. de Souza W (2002) From the cell biology to the development of new chemotherapeutic approaches against trypanosomatids: dreams and reality. Kinetoplastid Biol Dis 1:3PubMedCrossRefGoogle Scholar
  15. de Souza W, Rodrigues JC (2009) Sterol biosynthesis pathway as target for anti-trypanosomatid drugs. Interdisc Perspect Infect Dis 2009:642502Google Scholar
  16. de Souza EM, Lansiaux A, Bailly C et al (2004) Phenyl substitution of furamidine markedly potentiates its antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochem Pharmacol 68:593–600PubMedCrossRefGoogle Scholar
  17. de Souza EM, Menna-Barreto RFS, Araujo-Jorge TC et al (2006) Antiparasitic activity of aromatic diamidines is related to apoptosis-like death in Trypanosoma cruzi. Parasitology 133:75–79PubMedCrossRefGoogle Scholar
  18. Detmer E, Hemphill A, Müller N et al (1997) The Trypanosoma brucei autoantigen I/6 is an internally repetitive cytoskeletal protein. Eur J Cell Biol 72:378–384PubMedGoogle Scholar
  19. El-Sayed NM, Myler PJ, Bartholomeu DC et al (2005) The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309:409–415PubMedCrossRefGoogle Scholar
  20. Ennes-Vidal V, Menna-Barreto RF, Santos ALS et al (2010) Effects of the calpain inhibitor MDL28170 on the clinically relevant forms of Trypanosoma cruzi in vitro. J Antimicrob Chemother 65:1395–1398PubMedCrossRefGoogle Scholar
  21. Ennes-Vidal V, Menna-Barreto RF, Santos ALS et al (2011) MDL28170, A calpain inhibitor, affects Trypanosoma cruzi metacyclogenesis, ultrastructure and attachment to rhodnius prolixus midgut. PLoS One 6:e18371PubMedCrossRefGoogle Scholar
  22. Ersfeld K, Barraclough H, Gull K (2005) Evolutionary relationships and protein domain architecture in an expanded calpain superfamily in kinetoplastid parasites. J Mol Evol 61:742–757PubMedCrossRefGoogle Scholar
  23. Fang J, Beattie DS (2003) Alternative oxidase present in procyclic Trypanosoma brucei may act to lower the mitochondrial production of superoxide. Arch Biochem Biophys 414:294–302PubMedCrossRefGoogle Scholar
  24. Ferella M, Nilsson D, Darban H et al (2008) Proteomics in Trypanosoma cruzi-localization of novel proteins to various organelles. Proteomics 8:2735–2749PubMedCrossRefGoogle Scholar
  25. Fernandes MC, da Silva EN, Pinto AV et al (2012) A novel triazolic naphthofuranquinone induces autophagy in reservosomes and impairment of mitosis in Trypanosoma cruzi. Parasitology 139:26–36PubMedCrossRefGoogle Scholar
  26. Goll DE, Thompson VF, Li H et al (2003) The calpain system. Physiol Rev 83:731–801PubMedGoogle Scholar
  27. Gonçalves RLS, Menna-Barreto RFS, Polycarpo CR et al (2011) A comparative assessment of mitochondrial function in epimastigotes and bloodstream trypomastigotes of Trypanosoma cruzi. J Bioenerg Biomembr 43:651–661PubMedCrossRefGoogle Scholar
  28. Gonzales-Perdomo M, Romero P, Goldenberg S (1988) Cyclic AMP and adenylate cyclase activators stimulate Trypanosoma cruzi differentiation. Exp Parasitol 66:205–212PubMedCrossRefGoogle Scholar
  29. Holetz FB, Alves LR, Probst CM et al (2010) Protein and mRNA content of TcDHH1-containing mRNPs in Trypanosoma cruzi. FEBS J 277:3415–3426PubMedCrossRefGoogle Scholar
  30. Irigoín F, Cibils L, Comini MA et al (2008) Insights into the redox biology of Trypanosoma cruzi: trypanothione metabolism and oxidant detoxification. Free Radic Biol Med 45:733–742PubMedCrossRefGoogle Scholar
  31. Jannin J, Villa L (2007) An overview of Chagas disease treatment. Mem Inst Oswaldo Cruz 102(suppl 1):95–97PubMedCrossRefGoogle Scholar
  32. Kawano DF, Silva VB, Jorge DM et al (2011) Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 106:957–967PubMedGoogle Scholar
  33. Kikuchi SA, Sodré CL, Kalume DE et al (2010) Proteomic analysis of two Trypanosoma cruzi zymodeme 3 strains. Exp Parasitol 126:540–551PubMedCrossRefGoogle Scholar
  34. Kubata BK, Duszenko M, Kabututu Z et al (2000) Identification of a novel prostaglandin F synthase in Trypanosoma brucei. J Exp Med 192:1327–1337PubMedCrossRefGoogle Scholar
  35. Kubata BK, Kabututu Z, Nozaki T et al (2002) A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi. J Exp Med 196:1241–1251PubMedCrossRefGoogle Scholar
  36. Magalhães AD, Charneau S, Paba J et al (2008) Trypanosoma cruzi alkaline 2-DE: optimization and application to comparative proteome analysis of flagellate life stages. Proteome Sci 6:24PubMedCrossRefGoogle Scholar
  37. Marchini FK, de Godoy LM, Rampazzo RC et al (2011) Profiling the Trypanosoma cruzi phosphoproteome. PLoS One 6:e25381PubMedCrossRefGoogle Scholar
  38. Marin-Neto JA, Rassi A Jr, Avezum A Jr et al (2009) The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem Inst Oswaldo Cruz 104:319–324, Suppl. IPubMedCrossRefGoogle Scholar
  39. Menna-Barreto RFS, Henriques-Pons A, Pinto AV et al (2005) Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles. J Antimicrob Chemother 56:1034–1041PubMedCrossRefGoogle Scholar
  40. Menna-Barreto RFS, Corrêa JR, Pinto AV et al (2007) Mitochondrial disruption and DNA fragmentation in Trypanosoma cruzi induced by naphthoimidazoles synthesized from beta-lapachone. Parasitol Res 101:895–905PubMedCrossRefGoogle Scholar
  41. Menna-Barreto RFS, Laranja GAT, Silva MCC et al (2008) Anti-Trypanosoma cruzi activity of Pterodon Pubescens seed oil: Geranylgeraniol as the major bioactive component. Parasitol Res 103:111–117PubMedCrossRefGoogle Scholar
  42. Menna-Barreto RF, Corrêa JR, Cascabulho CM et al (2009a) Naphthoimidazoles promote different death phenotypes in Trypanosoma cruzi. Parasitology 136:499–510PubMedCrossRefGoogle Scholar
  43. Menna-Barreto RFS, Goncalves RL, Costa EM et al (2009b) The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction. Free Radic Biol Med 47:644–653PubMedCrossRefGoogle Scholar
  44. Menna-Barreto RFS, Salomão K, Dantas AP et al (2009c) Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron 40:157–168PubMedCrossRefGoogle Scholar
  45. Menna-Barreto RF, Beghini DG, Ferreira AT et al (2010) A proteomic analysis of the mechanism of action of naphthoimidazoles in Trypanosoma cruzi epimastigotes in vitro. J Proteomics 73:2306–2315PubMedCrossRefGoogle Scholar
  46. Miller RL, Sabourin CL, Krenitsky TA (1987) Trypanosoma cruzi adenine nucleoside phosphorylase. Purification and substrate specificity. Biochem Pharmacol 36:553–560PubMedCrossRefGoogle Scholar
  47. Murta SMF, Krieger MA, Montenegro LR 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. Mol Biochem Parasitol 146:151–162PubMedCrossRefGoogle Scholar
  48. Nakayasu ES, Gaynor MR, Sobreira TJ et al (2009) Phosphoproteomic analysis of the human pathogen Trypanosoma cruzi at the epimastigote stage. Proteomics 9:3489–3506PubMedCrossRefGoogle Scholar
  49. Nakayasu ES, Sobreira TJ, Torres R Jr et al (2012) Improved proteomic approach for the discovery of potential vaccine targets in Trypanosoma cruzi. J Proteome Res 11:237–246PubMedCrossRefGoogle Scholar
  50. Nwaka S, Hudson A (2006) Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov 5:941–955PubMedCrossRefGoogle Scholar
  51. Paba J, Santana JM, Teixeira AR et al (2004) Proteomic analysis of the human pathogen Trypanosoma cruzi. Proteomics 4:1052–1059PubMedCrossRefGoogle Scholar
  52. Parodi-Talice A, Durán R, Arrambide N et al (2004) Proteome analysis of the causative agent of Chagas’ disease: Trypanosoma cruzi. Int J Parasitol 34:881–886PubMedCrossRefGoogle Scholar
  53. Parodi-Talice A, Monteiro-Goes V, Arrambide N et al (2007) Proteomic analysis of metacyclic trypomastigotes undergoing Trypanosoma cruzi metacyclogenesis. J Mass Spectrom 42:1422–1432PubMedCrossRefGoogle Scholar
  54. Pérez-Morales D, Lanz-Mendoza H, Hurtado G et al (2012) Proteomic analysis of Trypanosoma cruzi epimastigotes subjected to heat shock. J Biomed Biotechnol 2012:902803PubMedCrossRefGoogle Scholar
  55. Piacenza L, Alvarez MN, Peluffo G et al (2009) Fighting the oxidative assault: the Trypanosoma cruzi journey to infection. Curr Opin Microbiol 12:415–421PubMedCrossRefGoogle Scholar
  56. Rassi A Jr, Rassi A, Marin-Neto JA (2009) Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Mem Inst Oswaldo Cruz 104:152–158, Suppl. IPubMedCrossRefGoogle Scholar
  57. Rocha MO, Teixeira MM, Ribeiro AL (2007) An update on the management of Chagas cardiomyopathy. Expert Rev Anti Infect Ther 5:727–743PubMedCrossRefGoogle Scholar
  58. Rocha GM, Teixeira DE, Miranda K et al (2010) Structural changes of the paraflagellar rod during flagellar beating in Trypanosoma cruzi. PLoS One 5:e11407PubMedCrossRefGoogle Scholar
  59. Rodrigues CO, Catisti R, Uyemura SA et al (2001) The sterol composition of Trypanosoma cruzi changes after growth in different culture media and results in different sensitivity to digitonin-permeabilization. J Eukaryot Microbiol 48:588–594PubMedCrossRefGoogle Scholar
  60. Rohloff P, Docampo R (2008) A contractile vacuole complex is involved in osmoregulation in Trypanosoma cruzi. Exp Parasitol 118:17–24PubMedCrossRefGoogle Scholar
  61. Romanha AJ, DeCastro SL, Soeiro MNC et al (2010) In vitro and in vivo experimental models to drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz 105:233–238PubMedCrossRefGoogle Scholar
  62. Salomão K, de Souza EM, Henriques-Pons A et al (2011) Brazilian green propolis: effects In vitro and In vivo on Trypanosoma cruzi. Evid Based Complement Alternat Med 2011:185918PubMedCrossRefGoogle Scholar
  63. Sant’Anna C, Nakayasu ES, Pereira MG et al (2009) Subcellular proteomics of Trypanosoma cruzi reservosomes. Proteomics 9:1782–1794PubMedCrossRefGoogle Scholar
  64. Santa-Rita RM, Barbosa HS, Meirelles MN et al (2000) Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi. Acta Trop 75:219–228PubMedCrossRefGoogle Scholar
  65. Santa-Rita RM, Lira R, Barbosa HS et al (2005) Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis. J Antimicrob Chemother 55:780–784PubMedCrossRefGoogle Scholar
  66. Santa-Rita RM, Barbosa HS, DeCastro SL (2006) Ultrastructural analysis of edelfosine-treated trypomastigotes and amastigotes of Trypanosoma cruzi. Parasitol Res 100:187–190PubMedCrossRefGoogle Scholar
  67. Schmunis GA (2007) Epidemiology of Chagas’ disease in non endemic countries: the role of international migration. Mem Inst Oswaldo Cruz 102:75–85PubMedCrossRefGoogle Scholar
  68. Shapiro TA, Englund PT (1995) The structure and replication of kinetoplast DNA. Annu Rev Microbiol 49:117–143PubMedCrossRefGoogle Scholar
  69. Silber AM, Colli W, Ulrich H et al (2005) Amino acid metabolic routes in Trypanosoma cruzi: possible therapeutic targets against Chagas disease. Curr Drug Targets Infect Disord 5:53–64PubMedCrossRefGoogle Scholar
  70. Silva CF, Batista MM, De Souza EM et al (2007) Cellular effects of reversed amidines on Trypanosoma cruzi. Antimicrob Agents Chemother 51:3803–3809PubMedCrossRefGoogle Scholar
  71. Silva RG, Vetticatt MJ, Merino EF et al (2011) Transition-state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine. J Am Chem Soc 133:9923–9931PubMedCrossRefGoogle Scholar
  72. Sodré CL, Chapeaurouge AD, Kalume DE et al (2009) Proteomic map of Trypanosoma cruzi CL brener: the reference strain of the genome project. Arch Microbiol 191:177–184PubMedCrossRefGoogle Scholar
  73. Soeiro MNC, DeCastro SL (2011) Screening of potential anti-Trypanosoma cruzi candidates: in vitro and in vivo studies. Open Med Chem J 5:21–30CrossRefGoogle Scholar
  74. Soeiro MNC, Daliry A, Silva CF et al (2010) Electron microscopy approaches for the investigation of the cellular targets of trypanocidal agents in Trypanosoma cruzi. In: Méndez-Vilas A, Díaz J (eds) Microscopy: science, technology, vol 4, Applications and education - microscopy book series. Formatex Research Center, Badajoz, pp 191–203, 1Google Scholar
  75. Sosa-Estani S, Viotti R, Segura EL (2009) Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina. Mem Inst Oswaldo Cruz 104(Suppl 1):167–180PubMedCrossRefGoogle Scholar
  76. Stoppani AO (1999) The chemotherapy of Chagas disease. Med (B Aires) 59:147–165Google Scholar
  77. Teixeira DE, Benchimol M, Crepaldi PH, de Souza W (2012) Interactive multimedia to teach the life cycle of Trypanosoma cruzi, the causative agent of Chagas disease. PLoS Negl Trop Dis 6:e1749PubMedCrossRefGoogle Scholar
  78. Tielens AG, Van Hellemond JJ (1998) Differences in energy metabolism between trypanosomatidae. Parasitol Today 14:265–272PubMedCrossRefGoogle Scholar
  79. Trapani S, Linss J, Goldenberg S et al (2001) Crystal structure of the dimeric phosphoenolpyruvate carboxykinase (PEPCK) from Trypanosoma cruzi at 2 a resolution. J Mol Biol 313:1059–1072PubMedCrossRefGoogle Scholar
  80. Ulrich PN, Jimenez V, Park M et al (2011) Identification of contractile vacuole proteins in Trypanosoma cruzi. PLoS One 6:e18013PubMedCrossRefGoogle Scholar
  81. Urbina JA (2009) Ergosterol biosynthesis inhibitors for the specific treatment of Chagas’ disease: 20 years after, does the promise holds? In: International symposium on the centennial of the discovery of Chagas’ Disease, Rio de JaneiroGoogle Scholar
  82. Urbina JA, Docampo R (2003) Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol 19:495–501PubMedCrossRefGoogle Scholar
  83. Vannier-Santos MA, DeCastro SL (2009) Electron microscopy in antiparasitic chemotherapy: a (close) view to a kill. Curr Drug Targets 10:246–260PubMedCrossRefGoogle Scholar
  84. Weatherly DB, Boehlke C, Tarleton RL (2009) Chromosome level assembly of the hybrid Trypanosoma cruzi genome. BMC Genomics 10:255PubMedCrossRefGoogle Scholar
  85. Zingales B, Andrade SG, Briones MR et al (2009) Second satellite meeting. A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz 104:1051–1054PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Laboratório de Biologia CelularInstituto Oswaldo Cruz, Fundação Oswaldo CruzRio de JaneiroBrazil
  2. 2.Laboratório de ToxinologiaInstituto Oswaldo Cruz, Fundação Oswaldo CruzRio de JaneiroBrazil

Personalised recommendations