Abstract:
Non-covalent recognition of glycans by galectins mediates or modulates numerous (patho)biological processes, including immune regulation, cancer, and fibrotic diseases. Using monovalent and polyvalent fluorinated carbohydrates is an attractive way to investigate glycan binding and develop selective inhibitors. In this grant proposal, we suggest chemical and/or chemoenzymatic synthesis of a series of fluorinated analogs of disaccharides lactose, N-acetyllactosamine, and N,N-diacetyllactosamine, and tetrasaccharide LacNAc1-3Lac and their use to investigate binding interactions with a panel of human galectins in both monovalent and multivalent (after attachment to dendrimers and proteins) settings. Kinetic and thermodynamic parameters of galectin binding will be determined, and the molecular basis of the binding phenomena and oligosaccharide conformation will be investigated by NMR methods. Based on recent findings by our team and others, we expect to modulate selectivity and affinity by deoxyfluorination and ligand clustering, and identify selective and high-affinity inhibitors.