title: The multivalent effect in glycosidase inhibition: probing the influence of valency, peripheral ligand structure, and topology with cyclodextrin-based iminosugar click clusters.
abstract: In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of β-CD-based multivalent iminosugars has been efficiently synthesized by way of Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). In combination with the first application of isothermal titration calorimetry (ITC) experiments to the study of multivalent iminosugar-enzyme interactions, the inhibition properties of these click clusters were evaluated on a panel of glycosidases. The structural parameters that were varied include valency, peripheral ligand structure, and topology. The inhibition results obtained with the iminosugar clusters further highlight the importance of multivalency in the inhibition of α-mannosidase. Generally, the evaluated multivalent iminosugars displayed comparable thermodynamic signatures of binding towards α-mannosidase (Jack bean): that is, large negative enthalpies of complexation coupled with small entropies of either sign. In addition, the enthalpy-entropy compensation observed in all tested cases may be attributed to a common mechanism of dissociation for the enzyme-multivalent iminosugar interactions. The measured binding stoichiometries indicated that each iminosugar cluster interacts with no more than one protein molecule.
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg (France).
authors.forename: Camille
authors.initials: C
authors.lastname: Decroocq
authors.forename: Antoine
authors.initials: A
authors.lastname: Joosten
authors.forename: Raphaël
authors.initials: R
authors.lastname: Sergent
authors.forename: Teresa
authors.initials: T
authors.lastname: Mena Barragán
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
mesh_terms: D057930:Click Chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D008024:Ligands; D047392:beta-Cyclodextrins; D006026:Glycoside Hydrolases
keywords: cyclodextrins; glycosidases; iminosugars; inhibitors; multivalency