The O-linked β-<i>N</i>-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs the GlcNAc moiety on thousands of intracellular proteins involved in various biological processes. Dysregulation of both OGT and O-GlcNAcylation have been observed in several human diseases including cancer, diabetes, and Alzheimer’s disease. However, due to the lack of conserved motif and a large pool of protein substrates, studying the roles of OGT in cells and disease models remains extraordinarily challenging. Specific, potent and cell-permeable inhibitors of OGT are much needed for understanding the functional roles of OGT. Following structure-based rational design, we have developed the first class of covalent inhibitors that irreversibly react with a unique cysteine in the active site of OGT. Our data from X-ray crystallization, biochemical assays and cellular characterizations demonstrated that the top candidate compounds inhibit OGT <i>in vitro</i> and in cells with high specificity and efficiency. Overall, our rational design of OGT inhibitors not only demonstrates an important concept to improve the potency and selectivity of OGT inhibition, but also provides a versatile tool to address the challenges of studying O-GlcNAcylation in cells.

Covalent inhibitors target O-GlcNAc transferase in cells

2019 Fall National Meeting

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