Estudo pré-clínico racional de novos candidatos a fármacos em protozooses negligen...
- Auxílios pontuais (curta duração)
| Texto completo | |
| 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: | 3 |
| 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 |