title: Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels.
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.
authors.affiliation: 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.
authors.forename: Mathieu L
authors.initials: ML
authors.lastname: Lepage
authors.affiliation: 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.
authors.forename: Jérémy P
authors.initials: JP
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Bodlenner
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II,132, 84084, Fisciano, Salerno, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Meli
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II,132, 84084, Fisciano, Salerno, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Riccardis
authors.affiliation: Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique (EA4466), ENSCMu, 3, rue Alfred Werner, 68093, Mulhouse Cedex, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique (EA4466), ENSCMu, 3, rue Alfred Werner, 68093, Mulhouse Cedex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Tarnus
authors.affiliation: Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes, UMR CNRS 7140, Université de Strasbourg, 67008, Strasbourg, France.
authors.forename: Nha-Thi
authors.initials: NT
authors.lastname: Nguyen-Huynh
authors.affiliation: Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes, UMR CNRS 7140, Université de Strasbourg, 67008, Strasbourg, France.
authors.forename: Yannis-Nicolas
authors.initials: YN
authors.lastname: Francois
authors.affiliation: Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes, UMR CNRS 7140, Université de Strasbourg, 67008, Strasbourg, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leize-Wagner
authors.affiliation: Structural Biology Platform, CBI-IGBMC, 1 rue Laurent Fries, 67404, Illkirch, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Birck
authors.affiliation: Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, 1 rue Laurent Fries, 67404, Illkirch CEDEX, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.affiliation: Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, 1 rue Laurent Fries, 67404, Illkirch CEDEX, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II,132, 84084, Fisciano, Salerno, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Izzo
authors.affiliation: 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.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0002-6877-0859
authors.initials: P
authors.lastname: Compain
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology; D050111:Imino Sugars / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D010456:Peptides, Cyclic / Q000737:chemistry*; D043323:alpha-Mannosidase / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D008024:Ligands; D010456:Peptides, Cyclic; D006026:Glycoside Hydrolases; D043323:alpha-Mannosidase
keywords: glycopeptides; glycosidases; iminosugars; inhibitors; multivalency