Journal
ISCIENCE
Volume 26, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2023.108144
Keywords
-
Categories
Ask authors/readers for more resources
This study aims to investigate the mechanism of action of an antileishmanial drug candidate VP343, and it was found that VP343 inhibits the survival of Leishmania infantum by interfering with host cell vesicular trafficking and cholesterol metabolism pathways.
Antileishmanial chemotherapy is currently limited due to severe toxic side effects and drug resistance. Hence, new antileishmanial compounds based on alternative approaches, mainly to avoid the emergence of drug resistance, are needed. The present work aims to decipher the mechanism of action of an antileish-manial drug candidate, named VP343, inhibiting intracellular Leishmania infantum survival via the host cell. Cell imaging showed that VP343 interferes with the fusion of parasitophorous vacuoles and host cell late endosomes and lysosomes, leading to lysosomal cholesterol accumulation and ROS overproduc-tion within host cells. Proteomic analyses showed that VP343 perturbs host cell vesicular trafficking as well as cholesterol synthesis/transport pathways. Furthermore, a knockdown of two selected targets involved in vesicle-mediated transport, Pik3c3 and Sirt2, resulted in similar antileishmanial activity to VP343 treatment. This work revealed potential host cell pathways and targets altered by VP343 that would be of interest for further development of host-directed antileishmanial drugs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available