Cell surface glycans are major determinants of cell-cell interactions. Changes In cell surface glycosylation mark the onset of cancer and inflammation. Inside the cell, they can regulate transcription, translation as well as protein trafficking. Progress toward delineating the molecular basis of glycan function, however, has been rather slow. This is partly due to the fact that the biosynthesis of glycans, unlike other biopolymers, is neither template-driven nor under direct transcriptional control. Therefore, conventional genetic and biochemical approaches for elucidating glycan function, and its relevance to disease, have yielded limited information. The long term goal of this project is to implement click chemistry-a set of powerful, reliable and selective reactions-as a general tool for fundamental studies of glycobiology. With the experience and knowledge gained from the K99 phase, I will expand my research in two new directions in the next granting period (ROO).
Aim 1 is to discover/develop small molecule inhibitors of glycan biosynthetic and processing enzymes using enzyme-templated in situ click chemistry. For proof of principle, I chose 0-beta-N-acetylglucosamlnyl-transferase (OGT) as the first target. I plan to develop fragment libraries that will be screened for self-assembled inhibitors of OGT. Given the correlation of excessive 0-GlcNAc modification with prolonged hyperglycemia, which in turn triggers insulin resistance, the compounds developed may have applications in diabetes therapy.
Aim 2 is to intercept glycan biosynthetic pathways with synthetic unnatural substrates bearing bioorthogonal functional groups, such as azides and alkynes. In parallel, I will also develop new selective reactions based on click chemistry for their subsequent detection in live cells.
Glycans are known to participate in many normal and disease processes. This series of experiments will advance our understanding of glycan biosynthesis and carbohydrate-protein interactions related to these disease states. These studies may also offer new avenues for therapeutic intervention. I anticipate that the new chemical tools developed in these studies will have broad applications in biomedical research.
| Rouhanifard, Sara H; Nordstrom, Lars Ulrik; Zheng, Tianqing et al. (2013) Chemical probing of glycans in cells and organisms. Chem Soc Rev 42:4284-96 |
| Li, Boyangzi; Mock, Feiyan; Wu, Peng (2012) Imaging the glycome in living systems. Methods Enzymol 505:401-19 |
| Besanceney-Webler, Christen; Jiang, Hao; Wang, Wei et al. (2011) Metabolic labeling of fucosylated glycoproteins in Bacteroidales species. Bioorg Med Chem Lett 21:4989-92 |
| Wang, Wei; Hong, Senglian; Tran, Andrew et al. (2011) Sulfated ligands for the copper(I)-catalyzed azide-alkyne cycloaddition. Chem Asian J 6:2796-802 |
| Besanceney-Webler, Christen; Jiang, Hao; Zheng, Tianqing et al. (2011) Increasing the efficacy of bioorthogonal click reactions for bioconjugation: a comparative study. Angew Chem Int Ed Engl 50:8051-6 |
| Soriano del Amo, David; Wang, Wei; Besanceney, Christen et al. (2010) Chemoenzymatic synthesis of the sialyl Lewis X glycan and its derivatives. Carbohydr Res 345:1107-13 |
| Soriano Del Amo, David; Wang, Wei; Jiang, Hao et al. (2010) Biocompatible copper(I) catalysts for in vivo imaging of glycans. J Am Chem Soc 132:16893-9 |
| Chang, Pamela V; Chen, Xing; Smyrniotis, Chris et al. (2009) Metabolic labeling of sialic acids in living animals with alkynyl sugars. Angew Chem Int Ed Engl 48:4030-3 |
