Grant: Discovery Grants Program - Individual

Our interdisciplinary research program focuses on the chemical biology of complex oligosaccharides with particular emphasis on two specific areas; conjugate vaccines and molecular recognition events that employ multivalency and supramolecular effects. The NSERC discovery grant is used to support research for the discovery and development of robust chemical methods to create and chemically define novel, biological active, compounds with potential for drug development. The target conjugate vaccine antigens are microbial cell wall oligosaccharides and mammalian tumour associated glycolipids, especially gangliosides, lipid antigens that are known to afford protection against cancer when administered as vaccines. We are developing novel chemistry for highly efficient covalent bond formation between carbohydrate antigenic determinants and immunogenic proteins, while ensuring the antibody response is focused on carbohydrate rather than the tether that links the two parts of the vaccine. We employ simple synthetic substrates that closely resemblenatural lipid and apply in vitro or in vivo chemoenzymic synthesis to complete the biosynthetic transformation of our substrate into vaccine precursors. We have developed novel concepts in the design of inhibitors to block toxin binding to cell surface oligosaccharide receptors and we are expanding this concept to include other cell surface receptors. The approach employs pre-organized heterobivalent ligands in a defined polymeric array. Their exceptionally high activity depends on their ability to bring together two proteins that bind weakly to one half of the ligand but strongly when both ends of our molecule are engaged by each protein. The increase in binding strength can approach a million to one billion. Practical applications include protection from otherwise fatal doses of bacterial toxin such as E. coli O157 and targeting of malignant cells. This design concept has numerous potential applications that are not limited to carbohydrate head groups. We are cognizant of these possibilities and will not limit our investigation to purely carbohydrate recognition elements.