Chemistry-enabled glycoscience

ABSTRACT - “Chemistry-Enabled Glycoscience” Overall changes in glycosylation are associated with many human diseases. Cancer cells increase the levels of specific capping sugars on their surfaces, while levels of the intracellular glycan O-GlcNAc are lower in Alzheimer's disease. Some of these associative changes are being exploited as potential therapies. However, a deeper understanding of what glycosylation is doing to the biochemistry and function of the underlying proteins is still largely lacking. For example, thousands of proteins are modified by O-GlcNAc but the effects of the vast majority of these modifications are completely unknown. For several reasons - heterogeneity, multiple modification sites, low immunogenicity, etc. - traditional biological tools have limitations for glycosylation. We have built a research program centered around the development and application of chemistry-enabled approaches aimed at unanswered questions in glycoscience. For example, we have played an important role improving and applying bioorthogonal reporters of glycans in living systems. We are also leaders in the application of protein synthesis to generate site-specifically glycosylated proteins for for in vitro and even in vivo characterization. We plan to build upon these successes to a) generate and apply cell/ tissue-selective reporters and inhibitors of glycosylation, b) create activity based probes of monosaccharide biosynthesis, c & d) further understand the effects of O-GlcNAc on pathogenic protein-aggregation, and e) investigate the consequences of mucin glycans on apolipoproteins. In the next five years, we will have created and used new tools for glycoscience in living systems and further unraveled the mechanisms by which glycosylation changes the biology of important proteins in human diseases.