Fiche publication
Date publication
octobre 2014
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOURDERIOUX Aurélie
Tous les auteurs :
Snášel J, Nauš P, Dostál J, Hnízda A, Fanfrlík J, Brynda J, Bourderioux A, Dušek M, Dvořáková H, Stolaříková J, Zábranská H, Pohl R, Konečný P, Džubák P, Votruba I, Hajdúch M, Rezáčová P, Veverka V, Hocek M, Pichová I
Lien Pubmed
Résumé
Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D (1)H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites.
Mots clés
Adenine, analogs & derivatives, Adenosine Kinase, antagonists & inhibitors, Adenosine Triphosphate, metabolism, Antitubercular Agents, chemistry, Binding Sites, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis, drug effects, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Ribonucleosides, chemistry, Structure-Activity Relationship
Référence
J Med Chem. 2014 Oct 23;57(20):8268-79
