Developing O-GlcNAc transferase inhibitors - insights from substrate recognition

Abstract

The modification of Ser and/or Thr residues of multitude of nucleocytoplasmic proteins (> 1000) with -N-acetylglucosamine (O-GlcNAc / O-GlcNAcylation) is a highly dynamic and essential process in metazoa. The attachment and removal of the sugar residue is regulated by two antagonistic enzymes. The O-GlcNAc transferase (OGT), which adds the sugar onto protein substrates and the O-GlcNAc hydrolase (OGA), which removes it. Mass spectrometric analyses have shown that O-GlcNAc can be found on proteins involved in nearly all biological processes, including trafficking, transcription & translation, protein degradation and cell cycle progression. Furthermore, evidence suggest that misregulation of O-GlcNAcylation may result in pathogenesis, such as Alzheimer’s and diabetes. To elucidate the function of O-GlcNAc it is crucial to understand the regulation of OGT and OGA activity in biological systems. One way of understanding the role of O-GlcNAc is manipulating the global O-GlcNAc levels by modulating activity of both enzymes with chemical tools. Indeed, many potent and specific inhibitors of OGA have been reported and already widely used in studies to link its activity to various pathologies and biological functions. However, the arsenal of OGT inhibitors has yet to include compounds that allow the study of OGT activity in vivo and/or in cellulo, due to their lack in potency and specificity. Here we present preliminary data of a new set of UDP-peptide conjugates, based on a parent scaffold we reported recently, which inhibit OGT with low-µM potency and have been modified with cell penetrating peptide scaffolds to be used in in vivo / in cellulo studies.

Date of Award	2017
Original language	English
Awarding Institution	University of Dundee
Supervisor	Daan van Aalten (Supervisor)