Bisubstrate ether-linked uridine-peptide conjugates as O-GlcNAc transferase inhibitors

Abstract

The O -linked β- N -acetylglucosamine (O -GlcNAc) transferase (OGT) is a master regulator of installing O -GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins with varying functional classes including translational factors, transcription factors, signaling proteins, phosphate kinase are OGT substrates. Aberrant O-GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. The selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors having micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition.