Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2

Détails

ID Serval
serval:BIB_70D8E7E24A01
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2
Périodique
Chemmedchem
Auteur⸱e⸱s
Degel Bjoern, Staib Peter, Rohrer Sebastian, Scheiber Josef, Martina Erika, Buechold Christian, Baumann Knut, Morschhaeuser Joachim, Schirmeister Tanja
ISSN
1860-7179
Statut éditorial
Publié
Date de publication
2008
Volume
3
Numéro
2
Pages
302-315
Langue
anglais
Résumé
A series of cis-configured epoxides and aziridines containing hydrophobic moieties and amino acid esters,were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans. Enzyme assays revealed the N- benzyl-3-phenyl-substituted aziridines 11 and 17 as the most potent inhibitors, with second-order inhibition, rate constants (k(2)) between 56000 and 12-1000 M-1 min(-1). The compounds were shown to be pseudo-irreversible dual-mode, inhibitors: the interm ediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition state-mimetic reversible inhibitors. The results of docking studies with the ring-closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1' S2, and S2' subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2-dependent growth while not affecting SAP2-independent growth.
Mots-clé
aspartic proteases, aziridines, Candida albicans, epoxides, inhibitors, Hiv-1 Protease, Ethyl (Diarylphosphono)Acetates, Cysteine Proteases, Antifungal Agents, Potent Inhibitor, Epoxide, Acid, Proteinases, Design, Peptidomimetics
Web of science
Création de la notice
13/10/2009 11:08
Dernière modification de la notice
20/08/2019 14:29
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