Abstract:
Non-covalent recognition of glycans by galectins mediate or modulate numerous (patho)
biological processes including immune regulation, cancer, and fibrotic diseases. Using
monovalent and polyvalent fluorinated carbohydrates has emerged as an attractive way to
investigate glycan binding and develop selective inhibitors. In this grant proposal, we suggest
chemical and/or chemoenzymatic synthesis of 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) setting. Kinetic and
thermodynamic parameters of galectin binding will be determined and molecular basis of the
binding phenomena and oligosaccharide conformation investigated by NMR methods. On the
basis of 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.