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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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