Identification of Inhibitors to Trypanosoma cruzi Sirtuins Based on Compounds Developed to Human Enzymes

Author(s):Show less -

Matutino Bastos, Tanira ^[1] ; Botelho Pereira Soares, Milena ^[1] ; Haddad Franco, Caio ^[2] ; Alcantara, Laura ^[2] ; Antonini, Lorenzo ^{[3, 4]} ; Sabatino, Manuela ^{[3, 4]} ; Mautone, Nicola ^{[3, 4]} ; Holanda Freitas-Junior, Lucio ^[2] ; Moraes, Carolina Borsoi ^[2] ; Ragno, Rino ^{[3, 4]} ; Rotili, Dante ^[4] ; Schenkman, Sergio ^[5] ; Mai, Antonello ^{[4, 6]} ; Silvio Moretti, Nilmar ^[5]

Affiliation

^[1] Fiocruz MS, Inst Goncalo Moniz, BR-40296710 Salvador, BA - Brazil

^[2] Univ Sao Paulo, Dept Microbiol, BR-05508900 Sao Paulo, SP - Brazil

^[3] Sapienza Univ Rome, Drug Chem & Technol Dept, Rome Ctr Mol Design, I-00185 Rome - Italy

^[4] Sapienza Univ Rome, Drug Chem & Technol Dept, I-00185 Rome - Italy

^[5] Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04039032 Sao Paulo, SP - Brazil

^[6] Sapienza Univ Rome, Cenci Bolognetti Fdn, Inst Pasteur, I-00161 Rome - Italy

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 10 MAY 2020.
• Web of Science Citations: 0

Abstract

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi, affecting more than 7 million people in the world. Benznidazole and nifurtimox are the only drugs available for treatment and in addition to causing several side effects, are only satisfactory in the acute phase of the disease. Sirtuins are NAD(+)-dependent deacetylases involved in several biological processes, which have become drug target candidates in various disease settings. T. cruzi presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against T. cruzi sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 (15 and 17), while other five inhibited TcSir2rp3 (8, 12, 13, 30, and 32), indicating that specific inhibitors can be devised for each one of the enzymes. Furthermore, all inhibiting compounds prevented parasite proliferation in cultured mammalian cells. When combining the most effective inhibitors with benznidazole at least two compounds, 17 and 32, demonstrated synergistic effects. Altogether, these results support the importance of exploring T. cruzi sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment. (AU)

• FAPESP's process: 18/09948-0 - Study of protein acetylation in Leishmania
• Grantee: Nilmar Silvio Moretti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/22031-0 - Cell signaling in Trypanosoma during host-parasite interaction
• Grantee: Sergio Schenkman
• Support Opportunities: Research Projects - Thematic Grants