Inhibiting Glycosylation

Glycosylation is termed as one of the most complex post-translational events. It mainly occurs intracellularly in the cellular compartments of Endoplasmic Reticulum and Golgi. More than 300 glycogenes participate in the process of glycosylation with around 200 of them being glycosyl-transferases and glycosidases. With the innovation in analytical sciences, various approaches have been used in the past decade to improve our understanding on glycobiology and its role in various biological phenomenon. Aberrant glycosylation induced by the differential expression of glycosyltransferases, glycosidases, sugar-nucleotide transporter, transcription factors, etc. causes anomalies in an otherwise normal physiology, resulting in aggravated conditions. While it is complicated to understand the global view of glycosylation in any particular diseased state, a mere focus on the role of glycosyltransferases (glycoTs) may help prevent disease state. To this end, various studies have identified individual or collective role of glycoTs thus hinting in the design of specific inhibitors targeting their function. Various attempts have been made in the past to design either glycoT inhibitors or sugar-nucleotide mimics, but have shown promising role only to a certain extend. To my knowledge, Talniflumate is the only known inhibitor which partially targets GCNT3 in addition to the mucins in vitro and in vivo. However, to extend these efforts a recent study by Soresen et al from the University of Copenhagen screened 1952 small-molecule compounds using HEK cells. Using gene KO systems, they proposed to discover specific-inhibitor for ppGalNAcT-11 but serendipitously ended up identifying global inhibitor for O-glycosylation, N-glycosylation and glycosaminoglycans. The authors utilized secretory Tn expressing LDL to measure the kinetics of these small-molecule compounds and determined its detailed mechanism governing reversible Golgi fragmentation. While this small-molecule library didn’t target specific glycoTs but the cellular systems generated to test these chemicals will have broader applications. However, it must be noted that this is a preliminary study and further experiments are required to prove the utility of these global inhibitors either in 3D cell culture or in vivo mice models.