Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease

Autor(es)

Moretti, Nilmar Silvio ^[1] ; Augusto, Leonardo da Silva ^[1] ; Clemente, Tatiana Mordente ^[1] ; Pinto Antunes, Raysa Paes ^[1] ; Yoshida, Nobuko ^[1] ; Torrecilhas, Ana Claudia ^[2] ; Nogueira Cano, Maria Isabel ^[3] ; Schenkman, Sergio ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Escola Paulista Med, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo - Brazil

^[3] Univ Estadual Paulista, Dept Genet, Inst Biociencias, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 59, n. 8, p. 4669-4679, AUG 2015.
• Citações Web of Science: 15

Resumo

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 mu M. We concluded that sirtuin inhibitors targeting TcSir2rp3 could be used in Chagas disease chemotherapy. (AU)

• Processo FAPESP: 09/54364-8 - Proteínas quinases e fosforilação de eIF2 envolvidas no crescimento e diferenciação de Trypanosoma cruzi
• Beneficiário: Leonardo da Silva Augusto
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 12/09403-8 - Estudo do papel das modificações de cromatina nos mecanismos de reparo de dano no DNA e controle da transcrição em Trypanosoma
• Beneficiário: Nilmar Silvio Moretti
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/51973-3 - Mecanismo de sinalização celular de Trypanosoma em resposta a alterações nutricionais e agentes genotóxicos
• Beneficiário: Sergio Schenkman
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/16211-0 - Estudo dos níveis de acetilação protéica em Trypanosoma cruzi
• Beneficiário: Raysa Paes Pinto Antunes
• Linha de fomento: Bolsas no Brasil - Iniciação Científica