Towards new glycosyltransferase ligands

Abstract

GalNAc‐T2 is an enzyme that catalyze the transfer of N-­Acetylgalactosamine from the donor substrate UDP‐GalNAc to the acceptor hydroxyl groups in mucine-‐type proteins. It belongs to a wide family of glycosyltransferase of which twenty isoforms are present in the human body. At the present time, despite the importance of this enzyme, involved in several metabolic disorders; very few binding substrates exists for this family of enzymes and no inhibitors have been reported. Here, we propose a new method to generate a new family of α-C‐glycoside ligands, based on the reactivity of the phosphonate group, miming the natural substrate but suppressing one phosphate function; leading to a new class of non‐too polar and non-­hydrolyzable compounds. We standardize the synthesis on a wide pool of different carbohydrates. Afterwards a docking study confirmed the binding capability of these new molecules with the GalNAc-­T2 enzyme and a biological assay and a crystal structure validated the in-­silico predicted binding capability. This method can be efficiently used to synthetize a wide variety of new compounds, and is easily extendable to different class of molecules and nucleosides to find new glycosyltransferase ligands.