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Design of Glycosyltransferase Inhibitors: Serine Analogues as Pyrophosphate Surrogates?
Shuai Wang1, Jose A Cuesta-Seijo2, Alexander Striebeck2
1Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246, CNRS and Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622, Villeurbanne, France.
Abstract:
Mimicking the diphosphate moiety of nucleotide diphosphate sugars with serine analogues provided modest glycosyltransferase inhibitors. The synthetic strategy employed a combination of glycosylation, amide bond formation and azide-alkyne "click" chemistry. Inhibition constants (Ki ) in the high micromolar range were obtained with a selection of five galactosyltransferases. Cocrystals of three inhibitors bound at the active site of a blood group A/B synthesizing glycosyltransferase were analysed. The structures and inhibitory patterns of the analogues demonstrate the flexibility of the enzymes which complicates the rational design of glycosyltransferase inhibitors.
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