Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | https://doi.org/10.1155/2018/8676578 http://hdl.handle.net/1843/60613 |
Resumo: | Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence. |
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2023-11-07T20:54:57Z2023-11-07T20:54:57Z20182018120https://doi.org/10.1155/2018/86765781942-0994http://hdl.handle.net/1843/60613Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.Devido às defesas antioxidantes rudimentares do Trypanosoma cruzi, os desreguladores do equilíbrio redox são candidatos promissores para novos fármacos antitripanossômicos. Desenvolvemos um modelo integrado baseado em revisão sistemática, meta-análises e modelagem molecular para avaliar o efeito dos inibidores da tripanotiona redutase (TR) nas infecções por T. cruzi. Nossos achados indicaram que os inibidores de TR analisados foram eficazes na redução da parasitemia e mortalidade por infecção por Trypanosoma cruzi em modelos animais. Os medicamentos mais investigados (clomipramina e tioridazina) não demonstraram efeitos benéficos na ocorrência de alterações eletrocardiográficas relacionadas à infecção ou na afinidade e densidade dos receptores β-adrenérgicos cardíacos. A afinidade entre os ligantes testados e o sítio ativo do TR foi confirmada por docking molecular. Entretanto, o escore de afinidade molecular não foi capaz de explicar a inibição do TR e a morte do T. cruzi in vitro ou o potencial antiparasitário dessas drogas quando testados em modelos pré-clínicos de infecção pelo T. cruzi. A divergência dos achados in silico, in vitro e in vivo indicou que o anti-T. cruzi dos medicamentos analisados não se restringiram à inibição do TR. Como os estudos in vivo sobre inibidores de TR ainda são escassos e apresentam limitações metodológicas, são necessários estudos mecanísticos e altamente controlados para melhorar a qualidade das evidências.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas GeraisengUniversidade Federal de Minas GeraisUFMGBrasilICB - DEPARTAMENTO DE MORFOLOGIAMED - DEPARTAMENTO DE CLÍNICA MÉDICAOxidative Medicine and Cellular LongevityTrypanosoma cruziInfecçãoInibidores enzimáticosTrypanosoma cruziInfecçãoInibidores enzimáticosRelevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approachRelevância dos inibidores da tripanotiona redutase na infecção pelo Trypanosoma cruzi: uma revisão sistemática, meta-análise e abordagem integrada in silicoinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220389/Andréa Aparecida Santos MendonçaCamila Morais CoelhoMarcia Paranho VelosoIvo Santana CaldasReggiani Vilela GonçalvesAntonio Lucio TeixeiraAline Silva de MirandaRômulo Dias Novaesapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/60613/1/License.txtfa505098d172de0bc8864fc1287ffe22MD51ORIGINALRelevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection A Systematic Review, Meta-Analysis, and In Silico Integrated Approach.pdfRelevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection A Systematic Review, Meta-Analysis, and In Silico Integrated Approach.pdfapplication/pdf4422589https://repositorio.ufmg.br/bitstream/1843/60613/2/Relevance%20of%20Trypanothione%20Reductase%20Inhibitors%20on%20Trypanosoma%20cruzi%20Infection%20A%20Systematic%20Review%2c%20Meta-Analysis%2c%20and%20In%20Silico%20Integrated%20Approach.pdf568527bdf9f68d56d4178aeccddcb911MD521843/606132023-11-07 20:32:17.389oai:repositorio.ufmg.br:1843/60613Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-11-07T23:32:17Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
dc.title.alternative.pt_BR.fl_str_mv |
Relevância dos inibidores da tripanotiona redutase na infecção pelo Trypanosoma cruzi: uma revisão sistemática, meta-análise e abordagem integrada in silico |
title |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
spellingShingle |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach Andréa Aparecida Santos Mendonça Trypanosoma cruzi Infecção Inibidores enzimáticos Trypanosoma cruzi Infecção Inibidores enzimáticos |
title_short |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
title_full |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
title_fullStr |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
title_full_unstemmed |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
title_sort |
Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach |
author |
Andréa Aparecida Santos Mendonça |
author_facet |
Andréa Aparecida Santos Mendonça Camila Morais Coelho Marcia Paranho Veloso Ivo Santana Caldas Reggiani Vilela Gonçalves Antonio Lucio Teixeira Aline Silva de Miranda Rômulo Dias Novaes |
author_role |
author |
author2 |
Camila Morais Coelho Marcia Paranho Veloso Ivo Santana Caldas Reggiani Vilela Gonçalves Antonio Lucio Teixeira Aline Silva de Miranda Rômulo Dias Novaes |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Andréa Aparecida Santos Mendonça Camila Morais Coelho Marcia Paranho Veloso Ivo Santana Caldas Reggiani Vilela Gonçalves Antonio Lucio Teixeira Aline Silva de Miranda Rômulo Dias Novaes |
dc.subject.por.fl_str_mv |
Trypanosoma cruzi Infecção Inibidores enzimáticos |
topic |
Trypanosoma cruzi Infecção Inibidores enzimáticos Trypanosoma cruzi Infecção Inibidores enzimáticos |
dc.subject.other.pt_BR.fl_str_mv |
Trypanosoma cruzi Infecção Inibidores enzimáticos |
description |
Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018 |
dc.date.accessioned.fl_str_mv |
2023-11-07T20:54:57Z |
dc.date.available.fl_str_mv |
2023-11-07T20:54:57Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/60613 |
dc.identifier.doi.pt_BR.fl_str_mv |
https://doi.org/10.1155/2018/8676578 |
dc.identifier.issn.pt_BR.fl_str_mv |
1942-0994 |
url |
https://doi.org/10.1155/2018/8676578 http://hdl.handle.net/1843/60613 |
identifier_str_mv |
1942-0994 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
Oxidative Medicine and Cellular Longevity |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.publisher.initials.fl_str_mv |
UFMG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
ICB - DEPARTAMENTO DE MORFOLOGIA MED - DEPARTAMENTO DE CLÍNICA MÉDICA |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
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Universidade Federal de Minas Gerais (UFMG) |
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UFMG |
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UFMG |
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Repositório Institucional da UFMG |
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Repositório Institucional da UFMG |
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