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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate

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Autor(es):
Lima, Marta L. [1, 2, 3] ; Abengozar, Maria A. [2] ; Nacher-Vazquez, Montserrat [2] ; Martinez-Alcazar, Maria P. [3] ; Barbas, Coral [3] ; Tempone, Andre G. [1] ; Lopez-Gonzalvez, Angeles [3] ; Rivas, Luis [2]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Sao Paulo, SP - Brazil
[2] CSIC, CIB, Madrid - Spain
[3] Univ CEU San Pablo, Fac Farm, Ctr Metab & Bioanal CEMBIO, Madrid - Spain
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Antimicrobial Agents and Chemotherapy; v. 62, n. 12 DEC 2018.
Citações Web of Science: 5
Resumo

Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against Leishmania share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in Leishmania were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on Leishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on the bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in L. infantum promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as a shortage of intracellular amino acids used as metabolic fuel by Leishmania. Sertraline killed Leishmania through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy. (AU)

Processo FAPESP: 15/23403-9 - Estudo pré-clínico racional de novos candidatos a fármacos em protozooses negligenciadas utilizando abordagens farmacocinéticas
Beneficiário:André Gustavo Tempone Cardoso
Linha de fomento: Auxílio à Pesquisa - Regular