Bundle, David R. - University of Alberta

研究领域

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. Antibodies against microbial carbohydrate antigens afford protection against infection and protein oligosaccharide conjugate vaccines are one of the most successful public health measures against serious diseases. Other important protein carbohydrate interactions involve adherence of bacteria or their toxins to the mammalian cell surface oligosaccharides of glycolipids, and N-linked and O-linked glycoproteins. The group currently focuses on two major themes: design, synthesis and evaluation of conjugate vaccines against bacterial and fungal diseases and the development of novel approaches for the design and synthesis of inhibitors to block bacterial toxin and virus binding to mammalian cells. The approach adopted is multidisciplinary and involves the synthesis of oligosaccharide epitopes generally consisting of 2-5 hexose residues, and NMR experiments to determine solution conformation in the free and bound states. 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. Research on toxin inhibitors involves a large component of computational approaches and molecular modeling studies. Our laboratory is part of the Alberta Ingenuity Centre for Carbohydrate Science. Several of our 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: Novel approaches in the design of conjugate vaccines to combat microbial infections "Candida albicans Conjugate Vaccines: Evaluation of synthetic beta-mannan oligosaccharides conjugated to immunogenic carriers in rabbit and mouse models of experimental candidiasis." "Multivalence assisted supramolecular assembly in biological systems."

近期论文

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Guiard, J., Paszkiewicz, E., Sadowska, J .M. and Bundle, D. R. Design and Synthesis of a Universal Antigen to Detect Brucellosis. Angew. Chem. Int. Ed., http://dx.doi.org/10.1002/anie.201302303.Published online 7th June 2013. Jacobson, J. M., Kitov, P. I. and Bundle, D. R. The Synthesis of a Multivalent Heterobifunctional Ligand for Specific Interaction with Shiga toxin 2 produced by E. coli O157:H7. Carbohydr. Res., doi: http://dx.doi.org/10.1016/j.carres.2013.05.010. Published online 28 May 2013. Iynkkaran, I. and Bundle, D. R. Synthesis of a trisaccharide repeat of the zwitterionic Sp1 capsular polysaccharide utilizing 2-azido-4-benzylamino-4N,3-O-carbonyl-2,4,6-trideoxy-D-galactopyranosyl trichloroacetimidate. Carbohydr. Res., doi:http://dx.doi.org/10.1016/j.carres.2013.05.005. Published online 21 May 2013. Lipinski, T., Fitieh, A., St. Pierre, J., Ostergaard, H. L., Bundle, D. R. and Touret, N. Enhanced Immunogenicity of a tricomponent mannan tetanus toxoid conjugate vaccine targeted to DCs via Dectin-1 by incorporating 尾-glucan. J. Immunol. in press, accepted Feb 21, 2013. Johnson, M. A. and Bundle, D. R. Designing a new antifungal glycoconjugate vaccine. Chem. Soc. Rev., DOI: 10.1039/c2cs35382b. Dang, A.-T., Johnson, M. A. and Bundle, D. R. Synthesis of a Candida albicans tetrasaccharide spanning the 尾1,2-mannan phosphodiester 伪-mannan junction. Org. Biomol. Chem., 10, 8348-8360, 2012. Bundle, D. R., Nycholat, C., Costello, C., Rennie, R. and Lipinski, T. 聽聽Design of a Candida albicans disaccharide conjugate vaccine by reverse engineering a protective monoclonal antibody. ACS Chem. Biol. 7, 1754-1763, 2012. Lipinski, T., Wu, X., Sadowska, J., Kreiter, E., Yasui, Y., Cheriaparambil, S., Rennie, R. and Bundle, D. R. A trisaccharide conjugate vaccine induces high titer 尾-mannan specific antibodies that aid clearance of Candida albicans in immunocompromised rabbits. Vaccine, 30, 6263-6269, 2012. Johnson, M. A., Cartmell, J., Weisser, N. E., Woods, R. J., and Bundle, D. R. 聽Molecular recognition of Candida albicans (1鈫�2)-尾-mannan oligosaccharides by a protective monoclonal antibody reveals the immunodominance of internal saccharide residue. J. Biol. Chem. 287, 18078-18090, 2012. Xin, H., Cartmell, J., Bailey, J. J., Dziadek, S., Bundle, D. R. and Cutler, J. E. Self -adjuvanting Glycopeptide Conjugate Vaccine against Disseminated Candidiasis. PLoS One 7, e35106, 2012. Costello, C. and Bundle, D. R. Synthesis of three trisaccharide congeners to investigate frame shifting of 尾1,2-mannan homo-oligomers in an antibody binding site. Carbohydr. Res., 357, 7-15, 2012. Zhang,P., Razi, N., Eugenio, L., Fentabil, M., Kitova, E.N., Klassen, J.S., Bundle, D.R., Ng, K.K.-S. and Ling, C.-C. Unexpected structure of a Clostridium difficile toxin A ligand necessitates an annotation correction in a popular screening library. Chem. Comm. 47, 12397-12399, 2011. Kitov, P. I., Paszkiewicz, E., Sadowska, J.M., Deng, Z., Ahmed, M., Narain, R., Griener, T., Mulvey, G. L., Armstrong, G. D., Bundle, D. R. Impact of the nature and size of the polymeric backbone on the ability of heterobifunctional ligands to mediate Shiga toxin and serum amyloid P component ternary complex formation. Toxins, 3, 1065-1088, 2011. Sandbhor, M. S., Soya, N, Albohy, A., Zheng, R. B., Cartmell, J., 聽Bundle, D. R., Klassen, 聽J. S. and Cairo, C. W. Substrate recognition of the membrane-associated sialidase NEU3 requires a hydrophobic aglycone. Biochemistry, 50, 6753-5762, 2011. Lipinski, T., Luu, T., Kitov, P. I., Szpacenko, A. and Bundle, D. R. A structurally diversified linker enhances the immune response to a small carbohydrate hapten. Glycoconj. J., 28, 149-164, 2011 Cui, L., Kitov, P. I., Completo, G. C., Paulson, J. C. and Bundle. D. R. Supramolecular Complexing of Membane Siglec CD22 Mediated by a Polyvalent Heterobifunctional Ligand that Templates on IgM. Bioconjug. Chem., 22, 546-550, 2011. Rademacher, C., Guiard, J., Kitov, P., Langpap, B., Dalton, K. P., Parra, F., Bundle, D. R. and Peters, P. Targeting Norovirus Infection 鈥� Multivalent Entry Inhibitor based on NMR Data. Chem. Eur. J., 17, 7442-7453, 2011. Guiard, J., Langpap, B., Kitov, P., Peters, P. and Bundle, D. R. “Double-Click” Protocol for Synthesis of Heterobifunctional Multivalent Ligands: Toward a Focused Library of Specific Norovirus Inhibitors. Chem. Eur. J., 17, 7438-7441, 2011. Tran, H.-A., Kitov,P. I., Paszkiewicz, E., Sadowska, J. M. and Bundle, D. R. Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists. Org. Biomol. Chem., 9, 3658-3671, 2011. Lipinski, T., Kitov, P., Szpacenko, A., Paszkiewicz, E. and Bundle, D. R. Synthesis and Immunogenicity of a Glycopolymer Conjugate. Bioconjug. Chem., 22, 274-281, 2011.