Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD(+)-dependent class III histone deacetylase, to interfere with the parasites’...

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Autores principales: Ferreira, Glaucio Monteiro, Kronenberger, Thales, Maltarollo, Vinicius Gonçalves, Poso, Antti, de Moura Gatti, Fernando, Almeida, Vitor Medeiros, Marana, Sandro Roberto, Lopes, Carla Duque, Tezuka, Daiane Yukie, de Albuquerque, Sérgio, da Silva Emery, Flavio, Trossini, Gustavo Henrique Goulart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10057528/
https://www.ncbi.nlm.nih.gov/pubmed/36986527
http://dx.doi.org/10.3390/ph16030428
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author Ferreira, Glaucio Monteiro
Kronenberger, Thales
Maltarollo, Vinicius Gonçalves
Poso, Antti
de Moura Gatti, Fernando
Almeida, Vitor Medeiros
Marana, Sandro Roberto
Lopes, Carla Duque
Tezuka, Daiane Yukie
de Albuquerque, Sérgio
da Silva Emery, Flavio
Trossini, Gustavo Henrique Goulart
author_facet Ferreira, Glaucio Monteiro
Kronenberger, Thales
Maltarollo, Vinicius Gonçalves
Poso, Antti
de Moura Gatti, Fernando
Almeida, Vitor Medeiros
Marana, Sandro Roberto
Lopes, Carla Duque
Tezuka, Daiane Yukie
de Albuquerque, Sérgio
da Silva Emery, Flavio
Trossini, Gustavo Henrique Goulart
author_sort Ferreira, Glaucio Monteiro
collection PubMed
description Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD(+)-dependent class III histone deacetylase, to interfere with the parasites’ cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC(50) = 40 μM) was chosen as a potential lead compound.
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spelling pubmed-100575282023-03-30 Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design Ferreira, Glaucio Monteiro Kronenberger, Thales Maltarollo, Vinicius Gonçalves Poso, Antti de Moura Gatti, Fernando Almeida, Vitor Medeiros Marana, Sandro Roberto Lopes, Carla Duque Tezuka, Daiane Yukie de Albuquerque, Sérgio da Silva Emery, Flavio Trossini, Gustavo Henrique Goulart Pharmaceuticals (Basel) Article Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD(+)-dependent class III histone deacetylase, to interfere with the parasites’ cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC(50) = 40 μM) was chosen as a potential lead compound. MDPI 2023-03-10 /pmc/articles/PMC10057528/ /pubmed/36986527 http://dx.doi.org/10.3390/ph16030428 Text en © 2023 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
Ferreira, Glaucio Monteiro
Kronenberger, Thales
Maltarollo, Vinicius Gonçalves
Poso, Antti
de Moura Gatti, Fernando
Almeida, Vitor Medeiros
Marana, Sandro Roberto
Lopes, Carla Duque
Tezuka, Daiane Yukie
de Albuquerque, Sérgio
da Silva Emery, Flavio
Trossini, Gustavo Henrique Goulart
Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title_full Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title_fullStr Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title_full_unstemmed Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title_short Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
title_sort trypanosoma cruzi sirtuin 2 as a relevant druggable target: new inhibitors developed by computer-aided drug design
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10057528/
https://www.ncbi.nlm.nih.gov/pubmed/36986527
http://dx.doi.org/10.3390/ph16030428
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