Mechanistic Insight into Heptosyltransferase Inhibition by using Kdo Multivalent Glycoclusters. Issue 37 (12th August 2016)

• Record Type: Journal Article
• Authors: Tikad, Abdellatif; Fu, Huixiao; Sevrain, Charlotte M.; Laurent, Sophie; Nierengarten, Jean‐François; Vincent, Stéphane P.
• Is Part Of: Chemistry. Volume 22:Issue 37(2016)
• Page Start: 13147
• Page End: 13155
• Publication Date: 2016-08-12
• Subjects: fullerenes -- glycoconjugates -- inhibitors -- receptors -- transferases; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201602190
• Languages: English
• ISSNs: 0947-6539

Abstract

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 ( K i =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. Abstract : Better together? The synthesis of unprecedented multimeric Kdo glycoclusters based on fullerene and calixarene central scaffolds is reported (see figure). The compounds were used to study the mechanism and the scope of multivalent heptosyltransferase inhibition, which is an important bacterial enzyme. The novel Kdo glycofullerenes displayed very potent inhibition ( K i =0.14 μm ), at a level that is rarely observed with glycosyltransferases.