Efficacy of sertraline against Trypanosoma cruzi: an in vitro and in silico study

Author(s):Show less -

Ferreira, Daiane Dias ^[1] ; Mesquita, Juliana Tonini ^[1] ; da Costa Silva, Thais Alves ^[1] ; Romanelli, Maiara Maria ^[1] ; Jaen Batista, Denise da Gama ^[2] ; da Silva, Cristiane Franca ^[2] ; Silva da Gama, Aline Nefertiti ^[2] ; Neves, Bruno Junior ^[3] ; Melo-Filho, Cleber Camilo ^[3] ; Correia Soeiro, Maria de Nazare ^[2] ; Andrade, Carolina Horta ^[3] ; Tempone, Andre Gustavo ^[1]

Affiliation

^[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Ave Dr Arnaldo 351, 8 Andar, Sala 9, BR-01246000 Sao Paulo, SP - Brazil

^[2] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Lab Biol Celular, Ave Brasil 4365, BR-21040360 Rio De Janeiro, RJ - Brazil

^[3] Univ Fed Goias, Fac Farm, Rua 240 Setor Leste Univ, BR-74605170 Goiania, Go - Brazil

• Document type: Journal article
• Source: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 24, OCT 30 2018.
• Web of Science Citations: 0

Abstract

Background: Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Methods: In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches. Results: Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 mu M, and activity against bloodstream trypomastigotes, with IC50 of 14 mu M. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline. Conclusions: The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds. (AU)

• FAPESP's process: 15/23403-9 - Rational pre-clinical study of new drug candidates against neglected protozoan diseases using pharmacokinetic approaches
• Grantee: André Gustavo Tempone Cardoso
• Support type: Regular Research Grants