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

Daiane Dias Ferreira,Andre Gustavo Tempone,Thais Alves Da Costa Silva,Cleber Camilo Melo-Filho,Bruno Junior Neves,Juliana Tonini Mesquita,Carolina Horta Andrade,Denise Da Gama Jaen Batista,Cristiane França Da Silva,Aline Nefertiti Silva Da Gama,Maiara Maria Romanelli,Maria De Nazare Correia Soeiro

doi:10.1186/s40409-018-0165-8

Abstract

BackgroundDrug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease.MethodsIn 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.ResultsSertraline 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.ConclusionsThe 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.

Highlights

Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease
Effects on mitochondrial integrity and adenosine triphosphate (ATP) production The mitochondrial integrity of trypomastigotes was investigated in the presence of SERT at the 50% inhibitory concentration (IC50) value using the fluorescent probe Mitotracker Red®
Carbonyl cyanide 4(trifluoromethoxy)phenylhydrazone (FCCP) was used as a positive control and reduced the fluorescence levels by approximately 54% compared to untreated parasites

Summary

Introduction

Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Chagas disease is a neglected tropical protozoan disease that affects 8 million people, mainly in South and Central America [1]; cases have been reported in North America, Europe and some other Western countries [2]. The current treatment of Chagas disease is an alarming issue. Several strategies have been implemented in order to reduce the costs and time of the drug discovery process. Drug repositioning has emerged as a promising strategy for drug discovery for Neglected Tropical Diseases (NTDs). The drug has shown promising activity against the protozoan Leishmania donovani; it reduced the parasite burden of animals by 72% at doses of 10 mg/kg for 30 days [11]

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Results

Conclusion