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Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds

Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds

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Original languageEnglish
Pages694-700
Number of pages7
JournalFEBS Letters
Journal publication date19 Feb 2010
Journal number4
Volume584
Early online date16/12/09
DOIs
StatePublished

Abstract

O-GlcNAcylation is an essential posttranslational modification in metazoa. Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. Here we report the discovery of novel, low molecular weight and drug-like O-GlcNAcase inhibitor scaffolds by high-throughput screening. Kinetic and X-ray crystallographic analyses of the binding modes with human/bacterial O-GlcNAcases identify some of these as competitive inhibitors. Comparative kinetic experiments with the mechanistically related human lysosomal hexosaminidases reveal that three of the inhibitor scaffolds show selectivity towards human OGA. These scaffolds provide attractive starting points for the development of non-carbohydrate, drug-like OGA inhibitors. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

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