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

TY - JOUR

T1 - Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds

A1 - Dorfmueller,Helge C.

A1 - van Aalten,Daan M. F.

AU - Dorfmueller,Helge C.

AU - van Aalten,Daan M. F.

PY - 2010/2/19

Y1 - 2010/2/19

N2 - <p>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.</p>

AB - <p>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.</p>

KW - O-GlcNAc

KW - Posttranslational modification

KW - Inhibitor

KW - Crystal structure

KW - Beta-N-acetylglucosaminidase

KW - Cell death

KW - linked GlcNAc

KW - Nucleocytoplasmic proteins

KW - Tetratricopeptide repeats

KW - Signal transduction

KW - Cytosolic proteins

KW - Ligand efficiency

KW - In vivo

KW - Streptozotocin

U2 - 10.1016/j.febslet.2009.12.020

DO - 10.1016/j.febslet.2009.12.020

M1 - Article

JO - FEBS Letters

JF - FEBS Letters

SN - 0014-5793

IS - 4

VL - 584

SP - 694

EP - 700

ER -