title: The inhibition of liposaccharide heptosyltransferase WaaC with multivalent glycosylated fullerenes: a new mode of glycosyltransferase inhibition.
abstract: L,D-Heptosides (L-glycero-D-manno-heptopyranoses) are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a series of fullerene hexa-adducts bearing 12 copies of peripheral sugars displaying the mannopyranose core structure of bacterial L,D-heptoside. The multimers were assembled through an efficient copper-catalyzed alkyne-azide cycloaddition reaction as the final step. The final fullerene sugar balls were assayed as inhibitors of heptosyltransferase WaaC, the glycosyltransferase catalyzing the incorporation of the first L-heptose into LPS. Interestingly, the inhibition of the final molecules was found in the low micromolar range (IC(50) =7-45 μM), whereas the corresponding monomeric glycosides displayed high micromolar to low millimolar inhibition levels (IC(50) always above 400 μM). When evaluated on a "per-sugar" basis, these inhibition data showed that, in each case, the average affinity of a single glycoside of the fullerenes towards WaaC was significantly enhanced when displayed as a multimer, thus demonstrating an unexpected multivalent effect. To date, such a multivalent mode of inhibition had never been evidenced with glycosyltransferases.
authors.affiliation: Chemistry Department, University of Namur (FUNDP) rue de Bruxelles 61, 5000 Namur, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Durka
authors.forename: Kevin
authors.initials: K
authors.lastname: Buffet
authors.forename: Julien
authors.initials: J
authors.lastname: Iehl
authors.forename: Michel
authors.initials: M
authors.lastname: Holler
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Nierengarten
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D037741:Fullerenes / Q000737:chemistry* / Q000494:pharmacology*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D037741:Fullerenes; D016695:Glycosyltransferases; C080934:lipooligosaccharide 1,5-heptosyltransferase