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Exploring the divalent effect in fucosidase inhibition with stereoisomeric pyrrolidine dimers

DOI: 10.1039/C6OB00647G DOI Help

Authors: Audrey Hottin (Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims) , Daniel Wright (University of York) , Elena Moreno-clavijo (Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla) , Antonio J. Moreno-vargas (Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla) , Gideon J. Davies (Structural Biology Laboratory Department of Chemistry, University of York, Diamond Light Source) , Jean-bernard Behr (Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Org. Biomol. Chem. , VOL 14 , PAGES 4718 - 4727

State: Published (Approved)
Published: April 2016
Diamond Proposal Number(s): 1221

Abstract: Multi-valent inhibitors offer promise for the enhancement of therapeutic compounds across a range of chemical and biological processes. Here, a significant increase in enzyme-inhibition potencies was observed with a dimeric iminosugar-templated fucosidase inhibitor (IC50 = 0.108 μM) when compared to its monovalent equivalent (IC50 = 2.0 μM). Such a gain in binding is often attributed to a “multivalent effect” rising from alternative recapture of the scaffolded binding epitopes. The use of control molecules such as the meso analogue (IC50 = 0.365 μM) or the enantiomer (IC50 = 569 μM), as well as structural analysis of the fucosidase-inhibitor complex, allowed a detailed analysis of the possible mechanism of action, at the molecular level. Here, the enhanced binding affinity of the dimer over the monomer can be attributed to additional interactions in non-catalytic sites as also revealed in the 3-D structure of a bacterial fucosidase inhibitor complex.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 05/09/2016 14:57

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