Faculty Research
Alphabetical · By research area

Mammalian cell surface oligosaccharides of glycolipids, and N-linked and O-linked glycoproteins mediate a variety of cell-cell interactions. This is accomplished through the interaction of the complex carbohydrate structures with proteins, either carbohydrate binding proteins or carbohydrate modifying enzymes. Research interests are centred on protein-carbohydrate interactions with particular emphasis on the relatively small carbohydrate recognition element (epitope) that contacts the protein binding site.

The approach adopted is multidisciplinary and involves the synthesis of oligosaccharide epitopes generally consisting of 3-5 hexose residues, and NMR experiments to determine solution conformation in the free and bound states. As far as possible the proteins under investigation (antibodies, enzymes and lectins) are cloned to ensure uniform properties and continuity of supply. To date we have concentrated on protein-oligosaccharide systems for which a high resolution crystal structure has been available. Special emphasis is placed on the accurate determination of the thermodynamics of binding using sensitive techniques such as titration microcalorimetry. The structure activity relationships that emerge are used to guide the design and synthesis of inhibitors. Some portions of the work rely on molecular modeling studies performed on Silicon Graphics work stations.

Our laboratory is part of the Alberta Ingenuity Centre for Carbohydrate Science (www.aiccs.com). Several of the group's projects involve national and international collaborations with crystallographers and bio-medical research groups. Current targets and practical applications of the research are synthesis of microbial antigens, glycolipid adjuvants, cancer associated glycosphingolipids, and the design and synthesis of high affinity inhibitors to block bacteria adherence or bacterial toxin binding to human cells. Examples of funded projects include:

• the development of a biosensor based on self assembled monolayers that present covalently attached oligosaccharides.
• "Targeted Cancer Vaccines: Synthesis and Evaluation of Clustered Melanoma Antigens."
• "Synthetic oligosaccharides and neutralization of ganglioside antibodies"
• "Candida albicans Conjugate Vaccines: Evaluation of synthetic beta-mannan oligosaccharides conjugated to immunogenic carriers in rabbit and mouse models of experimental candidiasis."
• "Design and Synthesis of Drugs to Treat Alzheimer Disease by Reduction of Serum Amyloid Protein and Amyloid Deposits."

Selected Publications

Kitov, P.I., Sadowska, J.M., Mulvey, G., Armstrong, G.D., Ling, H., Pannu, N.S., Read, R.J. and Bundle, D.R. "Shiga-like toxins neutralized by tailored multivalent carbohydrate ligands," Nature 2000, 403, 669-672.

Nitz, M., Ling, C. C., Otter, A., Cutler, J. E. and Bundle, D. R. "The unique solution structure and immunochemistry of the Candida albicans β-1,2-mannopyranan cell wall antigen," J. Biol. Chem. 2002, 277, 3440-3446.

Kitov, P.I. and Bundle, D.R. On the Nature of the Multivalency Effect: A Statistical Thermodynamic Model J. Am. Chem. Soc., 2003, 125, 16271-16284.

Ho, J.G.S., Kitov, P.I., Paszkiewicz, E., Sadowska, J., Bundle, D.R., and. Ng, K.K.-S. Ligand-assisted aggregation of proteins: dimerization of serum amyloid P component by bivalent ligands. J. Biol. Chem., 2005, 280, 31999-32008.

Bundle, D.R. Rich, J.R., Jacques, S., Yu, H.N., Nitz, M., and Ling, C.-C. Thio-oligosaccharide conjugate vaccines evoke antibodies specific for native antigens. Angew. Chem. Int. Ed., 2005, 44, 7725-7729.

Cai, Y., Ling, C.-C., and Bundle, D.R. A general, efficient and stereospecific route to sphingosine, sphinganines, phytosphingosines and their analogs. Org. Biomol. Chem., 2006, 4, 1140-1146.