PhD defence: The use of biological and computational tools to design, screen and synthesize new inhibitors of β-N-acetylglucosam

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O-GlcNAcylation is a post-translational modification occurring inside the cell on serine and threonine residues of proteins. These amino acids are modified on their hydroxyl function through the attachment of a β-N-acetylglucosamine moiety. It is regulated by two enzymes O-GlcNAc Transferase (OGT) that adds the GlcNAc moeity on the protein and O-GlcNAcase (OGA) that removes it. O-GlcNAcylation is involved in multiple biological processes due to the large number of proteins modified by it and its dysregulation has been flagged as an important step in degeneratve diseases such as cancer, diabetes and Alzheimer’s disease.

As a key part of the O-GlcNAcylation process, OGT is a potential therapeutic target and its inhibition will possibly enable new treatments for degenerative diseases. In this study, we investigated new ways to discover and assess OGT inhibitors. After implementing an assay to test ligands, we worked on different angles to improve existing or discover new OGT inhibitors. The use of computational tools like scaffold hopping provided us insights that a 6 member ring was needed to optimally mimic the uridine interaction with OGT.

In our last chapter we report the discovery of two new families of OGT inhibitors using a new screening tool: DNA encoded libraries. The synthesis and analysis of a small series of new compounds inspired by the screenings showed that these two new families are binding to OGT through a different binding mode than previously reported inhibitors.

Start date and time
End date and time
Location
Academiegebouw, Domplein 29 & online (livestream link)
PhD candidate
C. Balsollier
Dissertation
The use of biological and computational tools to design, screen and synthesize new inhibitors of β-N-acetylglucosaminyl transferase
PhD supervisor(s)
prof. dr. R.J. Pieters
prof. dr. M. Anderluh