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

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 ?M, and activity against bloodstream trypomastigotes, with IC50 of 14 ?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.

SUBMITTER: Ferreira DD

PROVIDER: S-EPMC6208092 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Efficacy of sertraline against <i>Trypanosoma cruzi</i>: an in vitro and in silico study.

Ferreira Daiane Dias DD Mesquita Juliana Tonini JT da Costa Silva Thais Alves TA Romanelli Maiara Maria MM da Gama Jaen Batista Denise D da Silva Cristiane França CF da Gama Aline Nefertiti Silva ANS Neves Bruno Junior BJ Melo-Filho Cleber Camilo CC Correia Soeiro Maria de Nazare MN Andrade Carolina Horta CH Tempone Andre Gustavo AG Tempone Andre Gustavo AG

The journal of venomous animals and toxins including tropical diseases 20181030

<h4>Background</h4>Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease.<h4>Methods</h4>In this work, we studied the activity of the antidepressant drug sertraline against <i>Trypanosoma cruzi</i> trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches.<h4>Results</h4>Sertraline demonstrated in vitro efficacy against intracel ...[more]

PMID: 30450114

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Project description:Chagas disease is a major health problem in Latin America, and an emerging infectious disease in the US. Previously, we have screened the Trypanosoma cruzi sequence database by a computational/bioinformatics approach, and identified antigens that exhibited the characteristics of vaccine candidates.We investigated the protective efficacy of a multi-component DNA-prime/protein-boost vaccine (TcVac2) constituted of the selected candidates and cytokine (IL-12 and GM-CSF) expression plasmids in a murine model. C57BL/6 mice were immunized with antigen-encoding plasmids plus cytokine adjuvants, followed by recombinant proteins; and two-weeks later, challenged with T. cruzi trypomastigotes. ELISA and flow cytometry were employed to measure humoral (antibody isotypes) and cellular (lymphocyte proliferation, CD4(+) and CD8(+) T cell phenotype and cytokines) responses. Myocardial pathology was evaluated by H&E and Masson's trichrome staining.TcVac2 induced a strong antigen-specific antibody response (IgG2b>IgG1) and a moderate level of lymphocyte proliferation in mice. Upon challenge infection, TcVac2-vaccinated mice expanded the IgG2b/IgG1 antibodies and elicited a substantial CD8(+) T cell response associated with type 1 cytokines (IFN-gamma and TNF-alpha) that resulted in control of acute parasite burden. During chronic phase, antibody response persisted, splenic activation of CD8(+) T cells and IFN-gamma/TNF-alpha cytokines subsided, and IL-4/IL-10 cytokines became dominant in vaccinated mice. The tissue parasitism, inflammation, and fibrosis in heart and skeletal muscle of TcVac2-vaccinated chronic mice were undetectable by histological techniques. In comparison, mice injected with vector or cytokines only responded to T. cruzi by elicitation of a mixed (type 1/type 2) antibody, T cell and cytokine response, and exhibited persistent parasite burden and immunopathology in the myocardium.TcVac2-induced activation of type 1 antibody and lymphocyte responses provided resistance to acute T. cruzi infection, and consequently, prevented the evolution of chronic immunopathology associated with parasite persistence in chagasic hearts.

Project description:Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 ?M for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 ?M). It was also active against the Colombiana strain (EC50= 3.8 ?M). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 ?M) was about 100-fold more active than Bz (2 ?M). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.

Dataset Information

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

Publications

Efficacy of sertraline against <i>Trypanosoma cruzi</i>: an in vitro and in silico study.

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