Design and synthesis of high affinity ligands: Univalent and polyvalent inhibitors of carbohydrate -protein interactions

Carbohydrates play an important role in intracellular and intercellular signalling via the molecular recognition by their receptor proteins. Hence, the study of carbohydrate-protein interactions is key to understanding and intervening in these biological events. The affinity of univalent carbohydrate-protein interactions is often weak, therefore design and synthesis of high affinity ligands would provide better insight into the carbohydrate-protein interactions, and offer potential therapeutics in the case of diseases, such as cancers and infections.;A monoclonal antibody IgG 9D4 raised against the glycan portion of the glycoprotein secreted by Trichinella spirallis can protect mice from further infection. The native terminal disaccharide of the glycan and its congeners were synthesized, and the affinity of the IgG antibody for these ligands was assessed.;High avidity ligands were created by using a multivalent IgM antibody scaffold or a polymer conjugate. Folate receptors are overexpressed on cancer cells. Heterobifunctional folate-GlcNAc ligands may be templated by an anti-G1cNAc IgM antibody and brought into a high avidity cell surface complex with folate receptors. A series of folate-GlcNAc conjugates were synthesized to optimize this process.;In the polymer-based approach, a polyvalent heterobifunctional ligand was synthesized and this successfully drove the self-assembly of IgM and siglec CD22 on malignant B cells. In comparison, its univalent ligand barely contributed to the complex formation. The affinity gain of the polyvalent ligand provides a general approach to driving high avidity complexes on cell surfaces, and specially a potential way to treat B lymphoma using polymeric therapeutics in the current project.;In this thesis, two approaches were explored to produce high affinity ligands. One of them applied functional group manipulation of univalent ligands, and the other employed multivalency to obtain high avidity ligands.