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Chemistry. 2016 Apr 4;22(15):5151-5. doi: 10.1002/chem.201600338. Epub 2016 Feb 24.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels.

Author information

1
Laboratoire de Synthèse Organique et Molécules Bioactives Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087, Strasbourg, France.
2
Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II,132, 84084, Fisciano, Salerno, Italy.
3
Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique (EA4466), ENSCMu, 3, rue Alfred Werner, 68093, Mulhouse Cedex, France.
4
Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes, UMR CNRS 7140, Université de Strasbourg, 67008, Strasbourg, France.
5
Structural Biology Platform, CBI-IGBMC, 1 rue Laurent Fries, 67404, Illkirch, France.
6
Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, 1 rue Laurent Fries, 67404, Illkirch CEDEX, France.
7
Laboratoire de Synthèse Organique et Molécules Bioactives Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087, Strasbourg, France. philippe.compain@unistra.fr.

Abstract

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

KEYWORDS:

glycopeptides; glycosidases; iminosugars; inhibitors; multivalency

PMID:
26917097
DOI:
10.1002/chem.201600338
[Indexed for MEDLINE]

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