title: Mechanistic Insight into Heptosyltransferase Inhibition by using Kdo Multivalent Glycoclusters.
abstract: The synthesis of unprecedented multimeric Kdo glycoclusters based on fullerene and calix[4]arene central scaffolds is reported. The compounds were used to study the mechanism and scope of multivalent glycosyltransferase inhibition. Multimeric mannosides based on porphyrin and pillar[5]arenes were also generated in a controlled manner. Twelve glycoclusters and their monomeric ligands were thus assayed against heptosyltransferase WaaC, which is an important bacterial glycosyltransferase that is involved in lipopolysaccharide biosynthesis. It was first found that all the multimers interact solely with the acceptor binding site of the enzyme even when the multimeric ligands mimic the heptose donor. Second, the novel Kdo glycofullerenes displayed very potent inhibition (Ki =0.14 μm for the best inhibitor); an inhibition level rarely observed with glycosyltransferases. Although the observed "multivalent effects" (i.e., the enhancement of affinity of a ligand when presented in a multimeric fashion) were in general modest, a dramatic effect of the central scaffold on the inhibition level was evidenced: the fullerene and the porphyrin scaffolds being by far superior to the calix- and pillar-arenes. We could also show, by dynamic light scattering analysis, that the best inhibitor had the propensity to form aggregates with the heptosyltransferase. This aggregative property may contribute to the global multivalent enzyme inhibition, but probably do not constitute the main origin of inhibition.
authors: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors: Abdellatif
authors: A
authors: Tikad
authors: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors: Huixiao
authors: H
authors: Fu
authors: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors: Charlotte M
authors: CM
authors: Sevrain
authors: University of Mons (UMONS), Service de Chimie Générale, Organique et Biomédicale, Laboratoire de RMN et d'Imagerie Moléculaire, Avenue Maistriau 19, 7000, Mons, Blegium.|Center for Microscopy and Molecular Imaging (CMMI), Avenue Adrienne Bolland 8, 6041, Gosselies, Belgium.
authors: Sophie
authors: S
authors: Laurent
authors: Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087, Strasbourg Cedex 2, France.
authors: Jean-François
authors: http://orcid.org/0000-0002-3333-9372
authors: JF
authors: Nierengarten
authors: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium. stephane.vincent@unamur.be.
authors: Stéphane P
authors: http://orcid.org/0000-0001-6258-9058
authors: SP
authors: Vincent
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D047250:Calixarenes / Q000737:chemistry*; D000067493:Dynamic Light Scattering / Q000379:methods; D037741:Fullerenes / Q000737:chemistry*; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D001426:Bacterial Proteins; D037741:Fullerenes; D008024:Ligands; D008070:Lipopolysaccharides; D011166:Porphyrins; D000644:Quaternary Ammonium Compounds; C570642:pillar(5)arene; D047250:Calixarenes; D016695:Glycosyltransferases; C086735:heptosyltransferase
keywords: fullerenes; glycoconjugates; inhibitors; receptors; transferases