An inhibitor of the human UDP-GlcNAc 4-epimerase identified from a uridine-based library:: A strategy to inhibit O-linked glycosylation

The biological study of O-linked glycosylation is particularly problematic, as chemical tools to control this modification are lacking. An inhibitor of the UDP-GIcNAc 4-epimerase that synthesizes UDP-GaINAc, the donor initiating O-linked glycosylation, would be a powerful reagent for reversibly inhibiting O-linked glycosylation. We synthesized a 1338 member library of uridine analogs directed to the epimerase by virtue,of substrate mimicry. Screening of the library identified an inhibitor with a K-i value of 11 muM. Tests:against related enzymes confirmed the compound's specificity for the UDP-GIcNAc 4-epimerase. Inhibitors of a key,step of O-linked glycan biosynthesis can be discovered from a directed library screen. Progeny thereof maybe powerful tools for controlling O-linked glycosylation in cells.