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

Other TitlesPDEs: therapeutic targets for leishmaniasis
AuthorsSebastián-Pérez, Víctor; Hendrickx, Sarah; Munday, Jane C.; Kalejaiye, Titilola; Martínez, Ana ; Campillo, Nuria E. ; Koning, Harry de; Caljon, Guy; Maes, Louis; Gil, Carmen
KeywordsDrug Discovery
Issue Date13-Aug-2018
PublisherAmerican Society for Microbiology
CitationAntimicrobial Agents and Chemotherapy 24:62(10) e00603-18 (2018)
AbstractThe 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.
Publisher version (URL)https://doi.org/10.1128/AAC.00603-18
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