Leishmaniasis y Enfermedad de Chagas: Herramientas para Nuevos Enfoques en su Tratamiento
DOI:
https://doi.org/10.32480/rscp.2019-24-1.126-136Palabras clave:
Leishmaniasis, Mal de Chagas, tripanotiona reductasa, tamizaje molecular virtualResumen
La Leishmaniasis y la Enfermedad de Chagas afectan a millones de personas en América Latina y en otras regiones del mundo, siendo las poblaciones rurales pobres y vulnerables las más afectadas. Aunque se han realizado esfuerzos conjuntos para el combate de estas enfermedades desatendidas, la combinación de diferentes factores como el tratamiento ineficiente, la falta de interés para invertir en la búsqueda de nuevas fuentes terapéuticas y el surgimiento de cepas de parásitos resistentes acaban complicando las perspectivas. Esta situación torna de vital importancia el desarrollo de nuevas estrategias que apunten a la identificación de moléculas con potencial aplicación en la terapia o que puedan ejercer un efecto sinérgico cuando se complementan con la quimioterapia actual. Uno de los enfoques propuestos para este fin consiste en la búsqueda de estos agentes basados en blancos farmacológicos presentes en los parásitos causantes de las citadas enfermedades. Entre estos blancos moleculares se encuentran las enzimas implicadas en vías esenciales del parásito, como la Tripanotiona Reductasa (TR), involucrada en el combate al estrés oxidativo generado por las especies reactivas de oxígeno producidas por macrófagos del huésped durante la infección. Una herramienta importante en la búsqueda de inhibidores para esta enzima puede ser encontrada a través de la aplicación de herramientas in silico, que resulta un método relativamente rápido y de bajo costo, el cual permite seleccionar moléculas con potencial a partir de una gran variedad de fuentes. Los ensayos basados en el tamizaje (“screening”) virtual permiten la selección de moléculas de forma racional, que mediante ensayos complementarios pueden dar lugar al surgimiento futuro de nuevos fármacos.
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Referencias
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12. Beig M, Oellien F, Krauth-Siegel RL, Selzer PM. Screening Approaches Towards Trypanothione Reductase. Trypanos Dis Mol Routes to Drug Discov. 2013;1-21.
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16. Polonio T, Efferth T. Leishmaniasis: Drug resistance and natural products (review). Int J Mol Med. 2008;22(3):277-86.
17. Colotti G, Baiocco P, Fiorillo A, Boffi A, Poser E, Chiaro F Di, et al. Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs. Future Med Chem. 2013 Oct;5(15):1861-75.
18. Fairlamb AH, Cerami A. Identification of a novel, thiol-containing co-factor essential for glutathione reductase enzyme activity in trypanosomatids. Mol Biochem Parasitol. 1985;14(2):187-98.
19. Fairlamb A, Blackburn P, Ulrich P, Chait B, Cerami A. Trypanothione: a novel bis (glutathionyl) spermidine cofactor for glutathione reductase in trypanosomatids. Science (80- ) [Internet]. 1985;227(4693):1485-7. Disponible en: http://www.sciencemag.org/content/227/4693/1485.short
20. Beig M, Oellien F, Garoff L, Noack S, Krauth-Siegel RL, Selzer PM. Trypanothione reductase: A target protein for a combined in vitro and in silico screening approach. Pollastri MP, editor. PLoS Negl Trop Dis. 2015 Jun;9(6):1-19.
21. Oliveira RB De, Zani CL, Ferreira RS, Leite RS, Silva THA, Carlos A, et al. Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase. 2008;31(2):261-7.
22. Kuriyan J, Kongt X-P, Krishna TSR, Sweett RM, Murgolo NJ, Field H, et al. X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution (glutathione reductase/oxidative stress/trypanosomiasls/protein crystaoraphy/drug design). Biochemistry. 1991;88(October):8764-8.
23. Cunningham ML, Fairlamb AH. Trypanothione reductase from Leishmania donovani - Purification, characterisation and inhibition by trivalent antimonials. Eur J Biochem. 1995;230(2):460-8.
24. Mukhopadhyay R, Mukherjee S, Mukherjee B, Naskar K, Mondal D, Decuypere S, et al. Characterisation of antimony-resistant Leishmania donovani isolates: Biochemical and biophysical studies and interaction with host cells. Int J Parasitol [Internet]. Australian Society for Parasitology Inc.; 2011;41(13–14):1311–21. Disponible en: http://dx.doi.org/10.1016/j.ijpara.2011.07.013
25. Benson TJ, McKie JH, Garforth J, Borges A, Fairlamb H, Douglas KT. Rationally designed selective inhibitors of trypanothione reductase: Phenothiazines and related tricyclics as lead structures. Biochem J. 1992;286:9-11.
26. Zilberstein D, Dwyer DM. Antidepressants Cause Lethal Disruption of Membrane Function in the Human Protozoan Parasite Leishmania. 1984;(November):977-9.
27. Mukherjee S, Mukherjee B, Mukhopadhyay R, Naskar K, Sundar S, Dujardin JC, et al. Imipramine Is an Orally Active Drug against Both Antimony Sensitive and Resistant Leishmania donovani Clinical Isolates in Experimental Infection. PLoS Negl Trop Dis. 2012;6(12).
28. Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH. Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: A template for drug design. J Biol Chem. 2004;279(28):29493–500.
29. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov [Internet]. 2005;4(3):206-20. Disponible en: http://www.nature.com/doifinder/10.1038/nrd1657
30. Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov. 2015;14(2):111–29.
31. Clardy J, Walsh C. Lessons from natural molecules. Nature. 2004;432(7019):829–37.
32. Tanrikulu Y, Krüger B, Proschak E. The holistic integration of virtual screening in drug discovery. Drug Discov Today. 2013;18(7–8):358-64.
33. Ferreira RS., Oliva G, Andricopulo AD. Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P & D de fármacos. Quim Nova. 2011;34(10):1770-8.
34. Blundell TL, Sibanda BL, Montalva RW, Brewerton S, Chelliah V, Worth CL, et al. Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Phil Trans R Soc B. 2006;361:413-423.
35. Nayeem A. A comparative study of available software for high-accuracy homology modeling: From sequence alignments to structural models. Protein Sci. 2006;15(4):808-24.
36. Durrant, J. D.; McCamon JA. Molecular dynamics simulations and novel drug discovery. BioMed Cent Biol. 2011;9(71):1-9.
37. Ma DL, Chan DS, Chung-Hang L. Molecular docking for virtual screening of natural product databases. Chem Sci. 2011;2:1656-65.
2. WHO-PAHO. Leishmaniases: Epidemiological Report of the Americas. Rep Leishmaniases [Internet]. 2013;1:1–4. Disponible en: http://iris.paho.org/xmlui/bitstream/handle/123456789/34858/LeishReport6_spa.pdf?sequence=5&isAllowed=y
3. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One [Internet]. 2012 Jan [citado 2014 Jul 16];7(5):e35671. Disponible en: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3365071&tool=pmcentrez&rendertype=abstract
4. Coura JR, Dias JCP. Epidemiology, control and surveillance of Chagas disease: 100 years after its discovery. Mem Inst Oswaldo Cruz. 2009 Jul;104(suppl 1):31-40.
5. Klug DM, Gelb MH, Pollastri MP. Repurposing strategies for tropical disease drug discovery. Bioorganic Med Chem Lett [Internet]. Elsevier Ltd; 2016;26(11):2569–76. Disponible en: http://dx.doi.org/10.1016/j.bmcl.2016.03.103
6. Tiuman TS, Santos AO, Ueda-Nakamura T, Filho BPD, Nakamura C V. Recent advances in leishmaniasis treatment. Int J Infect Dis [Internet]. 2011 Aug [citado 2014 Nov 11];15(8):e525-32. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/21605997
7. Müller J, Hemphill A. Drug target identification in protozoan parasites. Expert Opin Drug Discov. 2016;11(8):815-24.
8. Vijayakumar S, Das P. Recent progress in drug targets and inhibitors towards combating leishmaniasis. Acta Trop [Internet]. Elsevier B.V.; 2018;181:95–104. Disponible en: http://dx.doi.org/10.1016/j.actatropica.2018.02.010
9. Munos B. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov [Internet]. Nature Publishing Group; 2009;8(12):959–68. Disponible en: http://www.nature.com/doifinder/10.1038/nrd2961
10. Singh B, Sundar S. Leishmaniasis: Vaccine candidates and perspectives. Vaccine [Internet]. Elsevier Ltd; 2012;30(26):3834–42. Disponible en: http://dx.doi.org/10.1016/j.vaccine.2012.03.068
11. Comini MA, Flohé L. Trypanothione-Based Redox Metabolism of Trypanosomatids. In: Trypanosomatid Diseases: Molecular Routes to Drug Discovery. Germany: Wiley?VCH Verlag GmbH & Co. KGaA; 2013. p. 167–99.
12. Beig M, Oellien F, Krauth-Siegel RL, Selzer PM. Screening Approaches Towards Trypanothione Reductase. Trypanos Dis Mol Routes to Drug Discov. 2013;1-21.
13. Dias LC, Dessoy MA. Quimioterapia da doença de Chagas: Estado da arte e perspectivas no desenvolvimento de novos fármacos. Quim Nova. 2009;32(9):2444-57.
14. Frézard F, Demicheli C, Ribeiro RR. Pentavalent Antimonials: New Perspectives for Old Drugs. Molecules [Internet]. 2009 [citado 2014 Nov 19];14(7):2317–36. Disponible en: http://www.mdpi.com/1420-3049/14/7/2317/
15. Kaur G, Rajput B. Comparative analysis of the omics technologies used to study antimonial, amphotericin b, and pentamidine resistance in leishmania. J Parasitol Res. 2014;2014.
16. Polonio T, Efferth T. Leishmaniasis: Drug resistance and natural products (review). Int J Mol Med. 2008;22(3):277-86.
17. Colotti G, Baiocco P, Fiorillo A, Boffi A, Poser E, Chiaro F Di, et al. Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs. Future Med Chem. 2013 Oct;5(15):1861-75.
18. Fairlamb AH, Cerami A. Identification of a novel, thiol-containing co-factor essential for glutathione reductase enzyme activity in trypanosomatids. Mol Biochem Parasitol. 1985;14(2):187-98.
19. Fairlamb A, Blackburn P, Ulrich P, Chait B, Cerami A. Trypanothione: a novel bis (glutathionyl) spermidine cofactor for glutathione reductase in trypanosomatids. Science (80- ) [Internet]. 1985;227(4693):1485-7. Disponible en: http://www.sciencemag.org/content/227/4693/1485.short
20. Beig M, Oellien F, Garoff L, Noack S, Krauth-Siegel RL, Selzer PM. Trypanothione reductase: A target protein for a combined in vitro and in silico screening approach. Pollastri MP, editor. PLoS Negl Trop Dis. 2015 Jun;9(6):1-19.
21. Oliveira RB De, Zani CL, Ferreira RS, Leite RS, Silva THA, Carlos A, et al. Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase. 2008;31(2):261-7.
22. Kuriyan J, Kongt X-P, Krishna TSR, Sweett RM, Murgolo NJ, Field H, et al. X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution (glutathione reductase/oxidative stress/trypanosomiasls/protein crystaoraphy/drug design). Biochemistry. 1991;88(October):8764-8.
23. Cunningham ML, Fairlamb AH. Trypanothione reductase from Leishmania donovani - Purification, characterisation and inhibition by trivalent antimonials. Eur J Biochem. 1995;230(2):460-8.
24. Mukhopadhyay R, Mukherjee S, Mukherjee B, Naskar K, Mondal D, Decuypere S, et al. Characterisation of antimony-resistant Leishmania donovani isolates: Biochemical and biophysical studies and interaction with host cells. Int J Parasitol [Internet]. Australian Society for Parasitology Inc.; 2011;41(13–14):1311–21. Disponible en: http://dx.doi.org/10.1016/j.ijpara.2011.07.013
25. Benson TJ, McKie JH, Garforth J, Borges A, Fairlamb H, Douglas KT. Rationally designed selective inhibitors of trypanothione reductase: Phenothiazines and related tricyclics as lead structures. Biochem J. 1992;286:9-11.
26. Zilberstein D, Dwyer DM. Antidepressants Cause Lethal Disruption of Membrane Function in the Human Protozoan Parasite Leishmania. 1984;(November):977-9.
27. Mukherjee S, Mukherjee B, Mukhopadhyay R, Naskar K, Sundar S, Dujardin JC, et al. Imipramine Is an Orally Active Drug against Both Antimony Sensitive and Resistant Leishmania donovani Clinical Isolates in Experimental Infection. PLoS Negl Trop Dis. 2012;6(12).
28. Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH. Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: A template for drug design. J Biol Chem. 2004;279(28):29493–500.
29. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov [Internet]. 2005;4(3):206-20. Disponible en: http://www.nature.com/doifinder/10.1038/nrd1657
30. Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov. 2015;14(2):111–29.
31. Clardy J, Walsh C. Lessons from natural molecules. Nature. 2004;432(7019):829–37.
32. Tanrikulu Y, Krüger B, Proschak E. The holistic integration of virtual screening in drug discovery. Drug Discov Today. 2013;18(7–8):358-64.
33. Ferreira RS., Oliva G, Andricopulo AD. Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P & D de fármacos. Quim Nova. 2011;34(10):1770-8.
34. Blundell TL, Sibanda BL, Montalva RW, Brewerton S, Chelliah V, Worth CL, et al. Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Phil Trans R Soc B. 2006;361:413-423.
35. Nayeem A. A comparative study of available software for high-accuracy homology modeling: From sequence alignments to structural models. Protein Sci. 2006;15(4):808-24.
36. Durrant, J. D.; McCamon JA. Molecular dynamics simulations and novel drug discovery. BioMed Cent Biol. 2011;9(71):1-9.
37. Ma DL, Chan DS, Chung-Hang L. Molecular docking for virtual screening of natural product databases. Chem Sci. 2011;2:1656-65.
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1.
Leishmaniasis y Enfermedad de Chagas: Herramientas para Nuevos Enfoques en su Tratamiento. Rev. Soc. cient. Py. [Internet]. 2019 Jul. 6 [cited 2025 Jun. 15];24(1):126-3. Available from: http://sociedadcientifica.org.py/ojs/index.php/rscpy/article/view/61
