Date(s) - 09/10/2015
2:00 pm - 5:00 pm
Glycosylated Self-Assembled Nanofibers as Multivalent Galectin-3 Inhibitor
Carbohydrate recognition is an important phenomenon in many physiological and disease states. Cell surfaces and extracellular matrix are coated with glycans that interact with complementary proteins, including galectins, to dictate cell fate. In diseases like pancreatic cancer, the carbohydrate-galectin interface is altered by aberrant glycosylation of surface glycoproteins, which bind with high affinity to an upregulated galectin-3. This, in turn, results in a series of signaling events that lead to tumor progression and metastasis. The specifics of this interaction are poorly understood, primarily, due to the inherent heterogeneity of carbohydrate structures and the complexity of carbohydrate synthesis. Most current efforts to block the interaction between surface glycoproteins and galectin-3 focus on small molecule inhibitors. Despite their advantages, however, most saccharide ligands tend to bind to their protein receptor only weakly. Other efforts focus on multivalent glycan scaffolds, however, their efficacy is hindered by their complex chemical synthesis, and their unnatural display of sugar ligands, which ultimately limits the specificity of the glycomaterial for a target protein. Self-assembled glycopeptide nanofibers represent a novel glycomaterial for the inhibition of galectin-3. They are easy to produce with varying carbohydrate densities, and the carbohydrate chemistry can be easily tailored using sequential glycosyltransferase reactions. The guiding hypothesis of the proposed research is that glycopeptide self-assembly can be used to create biomaterials that can mimic natural surface glycoproteins with multivalently displayed ligands specific for galectin-3. Success of the proposed research will provide new tools to study fundamental aspects of carbohydrate-galectin interactions, and ultimately, will enable design of new therapeutic biomaterials to modulate galectin bioactivity.