Cyclic nucleotide specific phosphodiesterases as potential drug targets for anti-Leishmania therapy

Sebastián-Pérez, V., Hendrickx, S., Munday, J. C. , Kalejaiye, T., Martínez, A., Campillo, N. E., de Koning, H. , Caljon, G., Maes, L. and Gil, C. (2018) Cyclic nucleotide specific phosphodiesterases as potential drug targets for anti-Leishmania therapy. Antimicrobial Agents and Chemotherapy, 62(10), e00603-18. (doi:10.1128/AAC.00603-18) (PMID:30104270)

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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 have been postulated as putative drug targets, a series of potential inhibitors of PDEs was explored. Several displayed potent and selective activity against intracellular amastigotes. One imidazole derivative, compound , was shown to reduce the parasite loads and dose-dependently increase the cellular cAMP level at just 2× and 5× the IC , indicating a correlation between antileishmanial activity and increased cellular cAMP. Docking studies and molecular dynamics simulations pointed to imidazole 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:kalejaiye, Titilola and Munday, Dr Jane and De Koning, Professor Harry
Authors: Sebastián-Pérez, V., Hendrickx, S., Munday, J. C., Kalejaiye, T., Martínez, A., Campillo, N. E., de Koning, H., Caljon, G., Maes, L., and Gil, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Published Online:24 September 2018
Copyright Holders:Copyright © 2018 American Society for Microbiology
First Published:First published in Antimicrobial Agents and Chemotherapy 62(10): e00603-18
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY