Leishmaniasis and Chagas Disease: Tools for New Treatment Approaches
DOI:
https://doi.org/10.32480/rscp.2019-24-1.126-136Keywords:
Leishmaniasis, Chagas Disease, trypanothione reductase, virtual screeningAbstract
Leishmaniasis and Chagas disease affect millions of people worldwide, particularly in Latin America where poor and vulnerable rural populations are mostly affected. Although joint efforts have been made to fight these neglected diseases, the combination of different factors such as inefficient treatment, lack of interest in investing in the search for new therapeutic sources, and the emergence of resistant strains of parasites end up complicating prospects. This situation makes it vitally important to develop new strategies aimed at identifying molecules with potential application in therapy or that may exert a synergistic effect when supplemented with current chemotherapy. One of the approaches proposed for this purpose is the search for these agents based on pharmacological targets present in the parasites causing Leishmaniasis and Chagas. Among these molecular targets there are enzymes involved in essential pathways of the parasite, such as Trypanothione Reductase (TR), involved in combating oxidative stress generated by reactive oxygen species produced by host macrophages during infection. An important tool in the search for inhibitors for this enzyme can be found in the application of in silico tools, which is a relatively inexpensive and fast method of selecting potential molecules from a variety of sources. Assays based on virtual screening allow the selection of molecules in a rational way, which through complementary tests can lead to the future emergence of new drugs.
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References
1. WHO. Neglected tropical diseases [Internet]. 2019 [citado 2019 Mar 15]. Disponible en: https://www.who.int/neglected_diseases/diseases/en/
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.
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 and Chagas Disease: Tools for New Treatment Approaches. Rev. Soc. cient. Py. [Internet]. 2019 Jul. 6 [cited 2025 Oct. 7];24(1):126-3. Available from: http://sociedadcientifica.org.py/ojs/index.php/rscpy/article/view/61
