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The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Valency, Peripheral Ligand Structure, and Topology with Cyclodextrin‐Based Iminosugar Click Clusters
Author(s) -
Decroocq Camille,
Joosten Antoine,
Sergent Raphaël,
Mena Barragán Teresa,
Ortiz Mellet Carmen,
Compain Philippe
Publication year - 2013
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300283
Subject(s) - iminosugar , chemistry , isothermal titration calorimetry , valency , click chemistry , combinatorial chemistry , stereochemistry , crystallography , enzyme , biochemistry , philosophy , linguistics
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.