Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum

Sameh Obeid; Eloisa Berbel-Manaia; Valérie Nicolas; Indira Dennemont; Julien Barbier; Jean-Christophe Cintrat; Daniel Gillet; Philippe M Loiseau; Sébastien Pomel

doi:10.1016/j.isci.2023.108144

Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum

iScience. 2023 Oct 5;26(11):108144. doi: 10.1016/j.isci.2023.108144. eCollection 2023 Nov 17.

Authors

Sameh Obeid¹, Eloisa Berbel-Manaia¹, Valérie Nicolas², Indira Dennemont¹, Julien Barbier², Jean-Christophe Cintrat³, Daniel Gillet⁴, Philippe M Loiseau¹, Sébastien Pomel¹

Affiliations

¹ Université Paris-Saclay, CNRS BioCIS, 91400 Orsay, France.
² Université Paris-Saclay, UMS-IPSIT, Microscopy Facility, 92019 Châtenay-Malabry, France.
³ Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SCBM, 91191 Gif-sur-Yvette, France.
⁴ Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SIMoS, 91191 Gif-sur-Yvette, France.

Abstract

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 antileishmanial 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 overproduction 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.

Keywords: Cell biology; Drugs; Parasitology.