New Glycomimetics targeting Human GalNAc-T2, Synthesis, Computational and Structural Studies

Abstract

GalNAc-T2, is an enzyme belonging to the glycosyltransferase family that catalyzes the transfer of N-Acetylgalactosamine, from the donor substrate UDP-GalNAc to the acceptor hydroxyl groups in mucine-type proteins. This constitutes the most complex and well-regulated type of protein O-glycosylation, which present twenty different isoforms in the human body. Despite the important role that the protein plays, from health to metabolic disorders and disease, at the present time very few ligands have been reported, of which none is an effective inhibitor. In this work we propose a synthetic method directing to a new class of glycomimetic ligands, capable to bind the protein in the active site. These ligands leading to non-hydrolisable and less polar uridine-phosphonate derivatives, in which one phosphate function was suppressed and substitute by an alkyl chain, are by far more stable than the natural substrate. The synthetic method has been standardized on a wide pool of different carbohydrates; afterwards the protein binding capability was confirmed by a docking study and biological test too. Finally, a crystal structure of the complex [GalNAc-T2 – ligand] confirms the predicted binding capability, validating this method as a powerful and versatile tool in order to synthetize new glycosyltransferase inhibitors.