Identification of Inhibitors to Trypanosoma cruzi Sirtuins Based on Compounds Developed to Human Enzymes
Instituto Gonçalo Moniz, FIOCRUZ, Salvador 40296710, BA, Brazil
Departamento de Microbiologia, Universidade de São Paulo-USP, São Paulo 05508900, SP, Brazil
Rome Center for Molecular Design, Drug Chemistry and Technology Department, Sapienza University of Rome, 00185 Rome, Italy
Drug Chemistry and Technology Department, Sapienza University of Rome, 00185 Rome, Italy
Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039032, SP, Brazil
Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(10), 3659; https://doi.org/10.3390/ijms21103659
Received: 18 March 2020 / Revised: 25 April 2020 / Accepted: 26 April 2020 / Published: 22 May 2020
(This article belongs to the Special Issue Biochemistry, Molecular Biology and Druggability of Proteins)
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.