title: Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease.
abstract: Acetylation of lysine is a major posttranslational modification of proteins and is catalyzed by lysine acetyltransferases, while lysine deacetylases remove acetyl groups. Among the deacetylases, the sirtuins are NAD(+)-dependent enzymes, which modulate gene silencing, DNA damage repair, and several metabolic processes. As sirtuin-specific inhibitors have been proposed as drugs for inhibiting the proliferation of tumor cells, in this study, we investigated the role of these inhibitors in the growth and differentiation of Trypanosoma cruzi, the agent of Chagas disease. We found that the use of salermide during parasite infection prevented growth and initial multiplication after mammalian cell invasion by T. cruzi at concentrations that did not affect host cell viability. In addition, in vivo infection was partially controlled upon administration of salermide. There are two sirtuins in T. cruzi, TcSir2rp1 and TcSir2rp3. By using specific antibodies and cell lines overexpressing the tagged versions of these enzymes, we found that TcSir2rp1 is localized in the cytosol and TcSir2rp3 in the mitochondrion. TcSir2rp1 overexpression acts to impair parasite growth and differentiation, whereas the wild-type version of TcSir2rp3 and not an enzyme mutated in the active site improves both. The effects observed with TcSir2rp3 were fully reverted by adding salermide, which inhibited TcSir2rp3 expressed in Escherichia coli with a 50% inhibitory concentration (IC50) ± standard error of 1 ± 0.5 μM. We concluded that sirtuin inhibitors targeting TcSir2rp3 could be used in Chagas disease chemotherapy.
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Nilmar Silvio
authors.initials: NS
authors.lastname: Moretti
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: da Silva Augusto
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Tatiana Mordente
authors.initials: TM
authors.lastname: Clemente
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Raysa Paes Pinto
authors.initials: RP
authors.lastname: Antunes
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Departamento de Ciências Biológicas, Campus Diadema, Universidade Federal de São Paulo, Diadema, São Paulo SP, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Torrecilhas
authors.affiliation: Departamento de Genética, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil.
authors.forename: Maria Isabel Nogueira
authors.initials: MI
authors.lastname: Cano
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil sschenkman@unifesp.br.
authors.forename: Sergio
authors.initials: S
authors.lastname: Schenkman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D004260:DNA Repair / Q000187:drug effects; D008253:Macaca mulatta; D009284:Naphthols / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology*; D037761:Sirtuins / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: C539427:N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide; D009284:Naphthols; D010666:Phenylpropionates; D037761:Sirtuins