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). O-GlcNAcylation is involved in multiple biological processes due to the large amount of protein modified and its dysregulation has been flagged as an important step in degeneratve diseases such as cancer, diabetes…
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 are investigating now way to discover and assess new 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 allowed us to point that 6 member ring was needed to mimic 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 encode library. The synthesis of small libraries of these family coupled with our bioassay and molecular modeling showed that these two new families are binding to OGT through a different mechanism than the reported inhibitors.
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