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

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Serval ID
serval:BIB_70D8E7E24A01
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2
Journal
Chemmedchem
Author(s)
Degel Bjoern, Staib Peter, Rohrer Sebastian, Scheiber Josef, Martina Erika, Buechold Christian, Baumann Knut, Morschhaeuser Joachim, Schirmeister Tanja
ISSN
1860-7179
Publication state
Published
Issued date
2008
Volume
3
Number
2
Pages
302-315
Language
english
Abstract
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.
Keywords
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
Create date
13/10/2009 11:08
Last modification date
20/08/2019 14:29
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