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Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease
Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as syn...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863266/ https://www.ncbi.nlm.nih.gov/pubmed/36678516 http://dx.doi.org/10.3390/ph16010020 |
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author | Aguilera, Elena Sánchez, Carina Cruces, María Eugenia Dávila, Belén Minini, Lucía Mosquillo, Florencia Pérez-Díaz, Leticia Serna, Elva Torres, Susana Schini, Alicia Sanabria, Luis Vera de Bilbao, Ninfa I. Yaluff, Gloria Zolessi, Flavio R. Ceilas, Luis Fabian Cerecetto, Hugo Alvarez, Guzmán |
author_facet | Aguilera, Elena Sánchez, Carina Cruces, María Eugenia Dávila, Belén Minini, Lucía Mosquillo, Florencia Pérez-Díaz, Leticia Serna, Elva Torres, Susana Schini, Alicia Sanabria, Luis Vera de Bilbao, Ninfa I. Yaluff, Gloria Zolessi, Flavio R. Ceilas, Luis Fabian Cerecetto, Hugo Alvarez, Guzmán |
author_sort | Aguilera, Elena |
collection | PubMed |
description | Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease. |
format | Online Article Text |
id | pubmed-9863266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98632662023-01-22 Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease Aguilera, Elena Sánchez, Carina Cruces, María Eugenia Dávila, Belén Minini, Lucía Mosquillo, Florencia Pérez-Díaz, Leticia Serna, Elva Torres, Susana Schini, Alicia Sanabria, Luis Vera de Bilbao, Ninfa I. Yaluff, Gloria Zolessi, Flavio R. Ceilas, Luis Fabian Cerecetto, Hugo Alvarez, Guzmán Pharmaceuticals (Basel) Article Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease. MDPI 2022-12-23 /pmc/articles/PMC9863266/ /pubmed/36678516 http://dx.doi.org/10.3390/ph16010020 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Aguilera, Elena Sánchez, Carina Cruces, María Eugenia Dávila, Belén Minini, Lucía Mosquillo, Florencia Pérez-Díaz, Leticia Serna, Elva Torres, Susana Schini, Alicia Sanabria, Luis Vera de Bilbao, Ninfa I. Yaluff, Gloria Zolessi, Flavio R. Ceilas, Luis Fabian Cerecetto, Hugo Alvarez, Guzmán Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title | Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title_full | Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title_fullStr | Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title_full_unstemmed | Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title_short | Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease |
title_sort | preclinical studies and drug combination of low-cost molecules for chagas disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863266/ https://www.ncbi.nlm.nih.gov/pubmed/36678516 http://dx.doi.org/10.3390/ph16010020 |
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