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Exploiting the Hydrophobic Terrain in Fucosidases with Aryl-Substituted Pyrrolidine Iminosugars

DOI: 10.1002/cbic.201402509 DOI Help
PMID: 25427942 PMID Help

Authors: Audrey Hottin (Université de Reims Champagne-Ardenne) , Daniel Wright (University of York) , Gideon J. Davies (University of York) , Jean-bernard Behr (Université de Reims Champagne-Ardenne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chembiochem , VOL 16 (2) , PAGES 277 - 283

State: Published (Approved)
Published: January 2015
Diamond Proposal Number(s): 7864

Abstract: Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose-like iminosugars with hydrophobic “aglycons” yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2-aryl-3,4-dihydroxy-5-methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme–inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney (Ki=4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date.

Journal Keywords: Azasugars;Fucosidases;Hydrophobic Interactions;Inhibition;Structure

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 26/03/2015 16:40

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