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 > School of Infection & Immunity |
| 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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