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

Journal of venomous animals and toxins

Thais Alves da Costa Silva^1¹  Juliana Tonini Mesquita^1²  Maiara Maria Romanelli^1³  Daiane Dias Ferreira^1⁴ 

[1] Faculdade de Farmácia, Universidade Federal de Goiás, Rua 240 Setor Leste Universitário, Goiânia, GO 74605170 Brazil^3;Fundação Oswaldo Cruz, Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, CEP, Rio de Janeiro, RJ 21040-360 Brazil^2;Instituto Adolfo Lutz, Centre for Parasitology and Mycology, Avenida Dr. Arnaldo 351, 8° andar, sala 9, CEP, São Paulo, SP 01246-000 Brazil Find articles by Andre Gustavo Tempone^4;Instituto Adolfo Lutz, Centre for Parasitology and Mycology, Avenida Dr. Arnaldo 351, 8° andar, sala 9, CEP, São Paulo, SP 01246-000 Brazil^1

关键词: Trypanosoma cruzi;    Drug;    Treatment;    Sertraline;    Drug repurposing;    Drug repositioning;   

DOI  :  10.1186/s40409-018-0165-8

学科分类：药理学

来源: BioMed Central

【 摘 要 】

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 μM, and activity against bloodstream trypomastigotes, with IC₅₀ of 14 μM. 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 ( Tc IDH2) 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. Electronic supplementary material The online version of this article (10.1186/s40409-018-0165-8) contains supplementary material, which is available to authorized users.

【 授权许可】

CC BY