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’...

Descripción completa

Detalles Bibliográficos
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
Descripción
Sumario: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.

Ejemplares similares