Publication
Title
Cyclic nucleotide specific phosphodiesterases as potential drug targets for anti-Leishmania therapy
Author
Abstract
The available treatments for leishmaniasis are less than optimal due to inadequate efficacy, toxic side-effects and the emergence of resistant strains, clearly endorsing the urgent need for discovery and development of novel drug candidates. Ideally, these should act via an alternative mechanism-of-action to avoid cross-resistance with the current drugs. As cyclic nucleotide specific phosphodiesterases (PDEs) of L. major have been postulated as putative drug targets, a series of potential inhibitors of Leishmania PDEs was explored. Several displayed potent and selective in vitro activity against L. infantum intracellular amastigotes. One imidazole derivative, compound 35, was shown to reduce the parasite loads in vivo and dose-dependently increase the cellular cAMP level at just 2× and 5× the IC50, indicating a correlation between antileishmanial activity and increased cellular cAMP. Docking studies and molecular dynamics simulations pointed to imidazole 35 exerting its activity through PDE inhibition. This study establishes for the first time that inhibition of cAMP PDEs can potentially be exploited for new antileishmanial chemotherapy.
Language
English
Source (journal)
Antimicrobial agents and chemotherapy. - Washington, D.C., 1972, currens
Publication
Washington, D.C. : American Society for Microbiology , 2018
ISSN
0066-4804
Volume/pages
62 :10 (2018) , p. 1-12
ISI
000445405500015
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 30.08.2018
Last edited 20.01.2022
To cite this reference