Identification of Inhibitors to <i>Trypanosoma cruzi</i> Sirtuins Based on Compounds Developed to Human Enzymes

• Main Authors: Tanira Matutino Bastos, Milena Botelho Pereira Soares, Caio Haddad Franco, Laura Alcântara, Lorenzo Antonini, Manuela Sabatino, Nicola Mautone, Lucio Holanda Freitas-Junior, Carolina Borsoi Moraes, Rino Ragno, Dante Rotili, Sergio Schenkman, Antonello Mai, Nilmar Silvio Moretti
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: sirtuins; <i>Trypanosoma cruzi</i>; sirtuin inhibitors; deacetylation
• Online Access: https://www.mdpi.com/1422-0067/21/10/3659
• ISSN: 1661-6596; 1422-0067

Chagas disease is an illness caused by the protozoan parasite <i>Trypanosoma cruzi</i>, 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. <i>T. cruzi</i> presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against <i>T. cruzi</i> sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 (<b>15</b> and <b>17</b>), while other five inhibited TcSir2rp3 (<b>8</b>, <b>12</b>, <b>13</b>, <b>30</b>, and <b>32</b>), 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, <b>17</b> and <b>32</b>, demonstrated synergistic effects. Altogether, these results support the importance of exploring <i>T. cruzi</i> sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment.