title: Anti-Trypanosoma cruzi activity of nicotinamide.
abstract: Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic activity, indicating that these enzymes may be used as targets for drug discovery against trypanosomatid infections. In the present work we carried out a virtual screening focused on the C pocket of Sir2 from Trypanosoma cruzi. Using this approach, the best ligand found was nicotinamide. In vitro tests confirmed the anti-T. cruzi activity of nicotinamide on epimastigote and trypomastigote forms. Moreover, treatment of T. cruzi-infected macrophages with nicotinamide caused a significant reduction in the number of amastigotes. In addition, alterations in the mitochondria and an increase in the vacuolization in the cytoplasm were observed in epimastigotes treated with nicotinamide. Analysis of the complex of Sir2 and nicotinamide revealed the details of the possible ligand-target interaction. Our data reveal a potential use of TcSir2 as a target for anti-T. cruzi drug discovery.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, Salvador, BA, Brazil. milena@bahia.fiocruz.br
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
authors.forename: Cinara V
authors.initials: CV
authors.lastname: Silva
authors.forename: Tanira M
authors.initials: TM
authors.lastname: Bastos
authors.forename: Elisalva T
authors.initials: ET
authors.lastname: Guimarães
authors.forename: Claudio P
authors.initials: CP
authors.lastname: Figueira
authors.forename: Despina
authors.initials: D
authors.lastname: Smirlis
authors.forename: Walter F
authors.initials: WF
authors.lastname: Azevedo
mesh_terms: D000595:Amino Acid Sequence; D002470:Cell Survival; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology*; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000469:parasitology; D008958:Models, Molecular; D009536:Niacinamide / Q000494:pharmacology*; D015800:Protozoan Proteins; D016415:Sequence Alignment; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology
chemical_list: D008024:Ligands; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D009536:Niacinamide; D037761:Sirtuins