Fucosylated glycans are widely distributed throughout eukaryotes and certain bacteria. On the surface of mammalian cells, they mediate a variety of physiological and pathological processes, including angiogenesis, fertilization, embryogenesis, inflammation, and tumor metastasis. In pathogenic bacteria and parasites, fucosides regulate adhesion and colonization of host tissues and modulate the host immune response. Despite the obvious importance of fucosylated glycans, delineating the molecular basis of their function is severely hampered by their structural complexity and heterogeneity. Currently, there is no facile and cost-effective chemistry for synthesizing these glycans and their structurally related derivatives. The long term goal of this project is to develop new methods for the preparation of structurally defined fucosides and their derivatives and to fabricate new glycan array platforms for the comprehensive exploration of fucoside- protein interactions. In the first granting period, we will focus on three specific aims. First, we will develop a general chemoenzymatic strategy for preparative-scale synthesis of the universal fucosyl donor, guanidine 52- diphosphate-2-L-fucose (GDP-fucose), as well as chemically defined fucosides and their structurally related derivatives. We will harness fucosyl activation and transfer enzymes from bacterial sources to synthesize fucosylated glycans and glycoconjugates for their functional studies. Using the fucoside libraries generated in Aim 1, we will prepare a library of phospholipid-conjugated glycodendrimers and incorporate them into supported lipid bilayer membranes in a microarray format (Aim 2). The fluid nature of glycans in the planar lipid bilayer, coupled with the multivalent display, better mirrors the presentation of glycans found in nature as compared to the conventional immobilized monomeric glycans found in most arrays today. Access to structurally defined fucosides combined with the glycodendrimer microarray technology provides a powerful, rapid means to profile fucoside-protein interactions and to identify key structural features contributing to binding.
In Aim 3, we will use this technology to identify unnatural Lewis X derivatives with enhanced avidity for DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin), an important endocytic receptor mediating antigen presentation. The glycan ligands with enhanced DC-SIGN avidity identified from this study will be tested in vitro as targeting elements for delivering cargos to dendritic cells.
Fucosylated glycans are found on cell surfaces, where they play key roles in cell-cell interactions involved in normal biological processes and also in human disease. The goal of this research is to develop chemical tools for studying the biological functions of fucosylated glycans and glycoconjugates. These tools will improve our understanding of how these important glycans contribute to diseases such as cancer and inflammation. RELEVANCE / PROJECT NARRATIVE Fucosylated glycans are found on cell surfaces, where they play key roles in cell-cell interactions involved in normal biological processes and also in human disease. The goal of this research is to develop chemical tools for studying the biological functions of fucosylated glycans and glycoconjugates. These tools will improve our understanding of how these important glycans contribute to diseases such as cancer and inflammation.
|Cook, Ian; Wang, Ting; Wang, Wei et al. (2016) Controlling Sulfuryl-Transfer Biology. Cell Chem Biol 23:579-86|
|NordstrÃ¸m, Lars Ulrik; Sironi, Juan; Aranda, Evelyn et al. (2015) Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. ACS Med Chem Lett 6:134-9|
|Jiang, Hao; English, Brian P; Hazan, Rachel B et al. (2015) Tracking surface glycans on live cancer cells with single-molecule sensitivity. Angew Chem Int Ed Engl 54:1765-9|
|Feng, Lei; Jiang, Hao; Wu, Peng et al. (2014) Negative feedback regulation of Wnt signaling via N-linked fucosylation in zebrafish. Dev Biol 395:268-86|
|Rouhanifard, Sara H; LÃ³pez-Aguilar, AimÃ©; Wu, Peng (2014) CHoMP: a chemoenzymatic histology method using clickable probes. Chembiochem 15:2667-73|
|Jiang, Hao; Zheng, Tianqing; Lopez-Aguilar, Aime et al. (2014) Monitoring dynamic glycosylation in vivo using supersensitive click chemistry. Bioconjug Chem 25:698-706|
|Yang, Maiyun; Jalloh, Abubakar S; Wei, Wei et al. (2014) Biocompatible click chemistry enabled compartment-specific pH measurement inside E. coli. Nat Commun 5:4981|
|Zheng, Tianqing; Jiang, Hao; Wu, Peng (2013) Single-stranded DNA as a cleavable linker for bioorthogonal click chemistry-based proteomics. Bioconjug Chem 24:859-64|
|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|
|Zheng, Tianqing; Rouhanifard, Sara H; Jalloh, Abubakar S et al. (2012) Click Triazoles for Bioconjugation. Top Heterocycl Chem 28:163-183|
Showing the most recent 10 out of 17 publications