A convenient approach to stereoisomeric iminocyclitols: generation of potent brain-permeable OGA inhibitors

DOI: 10.1002/anie.201507985
PMID: 26545827

Authors: Milan Bergeron-Brlek (Simon Fraser University) , Jake Goodwin-Tindall (Simon Fraser University) , Nevena Cekic (Simon Fraser University) , Christian Roth (University of York) , Wesley F. Zandberg (Simon Fraser University) , Xiaoyang Shan (Simon Fraser University) , Vimal Varghese (Simon Fraser University) , Sherry Chan (University of York) , Gideon J. Davies (University of York) , David J. Vocadlo (Simon Fraser University) , Robert Britton (Simon Fraser University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: November 2015
Diamond Proposal Number(s): 9948

Abstract: Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.

Journal Keywords: Enzymes; Glycosides; Heterocycles; Hydrolases; Inhibitors

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 20/11/2015 14:41

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags: