title: Exploring the divalent effect in fucosidase inhibition with stereoisomeric pyrrolidine dimers.
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.
authors.affiliation: Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2, France. jb.behr@univ-reims.fr.
authors.forename: Audrey
authors.initials: A
authors.lastname: Hottin
authors.affiliation: Structural Biology Laboratory Department of Chemistry, University of York, York YO10 5DD, UK.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012 Sevilla, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Moreno-Clavijo
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012 Sevilla, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Moreno-Vargas
authors.affiliation: Structural Biology Laboratory Department of Chemistry, University of York, York YO10 5DD, UK.
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.affiliation: Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2, France. jb.behr@univ-reims.fr.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Behr
mesh_terms: D000818:Animals; D002417:Cattle; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D005644:alpha-L-Fucosidase; C032519:pyrrolidine