Current Research Interests: Bio-recognition: Carbohydrate-Protein Interactions
Oligosaccharides are fundamentally involved in important biological phenomena such as cell-cell adhesion, cell growth, inflammatory processes, fertilization, and bacterial, viral and parasitic infections. Our laboratory is active in understanding the underlying molecular mechanisms of carbohydrate-mediated recognition and in their exploitation for the design of improved immunodiagnostic reagents, vaccines, or therapeutic agents.
Our approach is based in part on a detailed knowledge of the structure and dynamics of oligosaccharides obtained by NMR and modeling studies. Such information derives from the direct examination by transferred NOE NMR experiments of ligand conformations when bound to protein receptors, complemented by molecular dynamics and Monte Carlo calculations. Information on bound conformations in the solid state is also obtained by X-ray crystallography of the receptor-ligand complexes (collaborations: F. Quiocho; S. Evans). Receptors under investigation include anti-carbohydrate antibodies directed against the cell-surface oligosaccharides of different pathogenic bacteria, and carbohydrate-processing enzymes such as the trans-sialidase enzyme of the parasite, Trypanosoma cruzi, the mutase responsible for pyranose to furanose interconversion, several mammalian glycoprotein-processing enzymes, and amylases from different species. Mechanistic information on the enzyme-catalyzed reactions is obtained by NMR spectroscopic analysis of binding events together with an analysis of intermediates and products formed in the reactions. An active synthetic program is used to furnish carbohydrates and carbohydrate-mimics that might function as inhibitors of particular carbohydrate-receptor interactions.
A particularly exciting aspect of the research program deals with the nature and origin of carbohydrate-peptide crossreactivity (collaboration: J.K. Scott). Our initial findings of such crossreactivity with antibody receptors has prompted us to expand our search to carbohydrate-processing enzyme receptors. The peptides and their cognate carbohydrates will be used together with well-defined receptors to probe, by NMR, molecular modeling, and X-ray crystallography, the nature of mimicry.