Design of Glycosyltransferase Inhibitors: Serine Analogues as Pyrophosphate Surrogates?

作者：Wang Shuai; Cuesta Seijo Jose A; Striebeck Alexander; Lafont Dominique; Palcic Monica M; Vidal Sebastien^*

来源：ChemPlusChem, 2015, 80(10): 1525-1532.

DOI：10.1002/cplu.201500282

• amino acids
• carbohydrates
• click chemistry
• glycosyltransferases
• inhibition

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 (K-i) 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.

• 出版日期2015-10