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

• Published in: Journal of Venomous Animals and Toxins including Tropical Diseases
• Main Authors: Daiane Dias Ferreira, Juliana Tonini Mesquita, Thais Alves da Costa Silva, Maiara Maria Romanelli, Denise da Gama Jaen Batista, Cristiane França da Silva, Aline Nefertiti Silva da Gama, Bruno Junior Neves, Cleber Camilo Melo-Filho, Maria de Nazare Correia Soeiro, Carolina Horta Andrade, Andre Gustavo Tempone
• Format: Article in Journal/Newspaper
• Language: English
• Published: SciELO 2018
• Subjects: Trypanosoma cruzi; Drug; Treatment; Sertraline; Drug repurposing; Drug repositioning; Arctic medicine. Tropical medicine; RC955-962; Toxicology. Poisons; RA1190-1270; Zoology; QL1-991; Arctic; The ''Y''
• Online Access: https://doi.org/10.1186/s40409-018-0165-8; https://doaj.org/article/5fea82da8c5541068b69e7ccd07d156e

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 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 (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.