title: Potent Glycosidase Inhibition with Heterovalent Fullerenes: Unveiling the Binding Modes Triggering Multivalent Inhibition.
abstract: Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase-lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a "recognition and blockage" mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature.
authors.affiliation: Département de Chimie, Laboratoire de Chimie Bio-Organique, University of Namur (UNamur), rue de Bruxelles 61, 5000, Namur, Belgium.
authors.forename: Marta
authors.initials: M
authors.lastname: Abellán Flos
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/Prof. García González 1, 41012, Sevilla, Spain.
authors.forename: M Isabel
authors.identifier: http://orcid.org/0000-0003-4273-3010
authors.initials: MI
authors.lastname: García Moreno
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/Prof. García González 1, 41012, Sevilla, Spain. mellet@us.es.
authors.forename: Carmen
authors.identifier: http://orcid.org/0000-0002-7676-7721
authors.initials: C
authors.lastname: Ortiz Mellet
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Av. Américo Vespucio 49, Isla de la Cartuja, 41092, Sevilla, Spain. jogarcia@iiq.csic.es.
authors.forename: Jose Manuel
authors.identifier: http://orcid.org/0000-0002-6827-0387
authors.initials: JM
authors.lastname: García Fernández
authors.affiliation: Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087, Strasbourg, France. nierengarten@unistra.fr.
authors.forename: Jean-Francois
authors.identifier: http://orcid.org/0000-0002-3333-9372
authors.initials: JF
authors.lastname: Nierengarten
authors.affiliation: Département de Chimie, Laboratoire de Chimie Bio-Organique, University of Namur (UNamur), rue de Bruxelles 61, 5000, Namur, Belgium. stephane.vincent@unamur.be.
authors.forename: Stéphane P
authors.identifier: http://orcid.org/0000-0001-6258-9058
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D037741:Fullerenes / Q000737:chemistry*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D037741:Fullerenes; D006026:Glycoside Hydrolases
keywords: binding modes; fullerenes; glycosidases; heterovalency; inhibitors