Carbohydrates are the most abundant family of natural products in nature and are frequently found conjugated with proteins, lipids, or other molecules. Adhesion, recognition, protein stability, transport and folding are all greatly influenced by saccharides. They are also important mediators of a variety of targeting and signaling processes. Current efforts are focused on the design and synthesis of transition-state analogs or mechanism-based inhibitors of enzymes associated with metabolic disorders or diseases. Mechanistic investigation and computer-assisted molecular modeling are important components for inhibitor design. It is our goal that analysis of mechanism-based inhibitors with enzymes and receptors will lead to identification of biologically relevant architectures as well as new therapeutic agents.
Figure 2A. Understanding the chemistry and biology of protein glycosylation is a major challenge in proteomic research. We are developing new methods to synthesize glycoproteins and to develop glycosyltransfer enzyme inhibitors.
Many of the projects in this laboratory involve the design and synthesis of small molecules to disrupt these targeting mechanisms, either via mimicry of the saccharide ligand or inhibition of glycosylation/ deglycosylation pathways. Various iminocyclitols and homoanalogs structurally related to monosaccharides have been prepared based on our chemical-enzymatic strategy for the synthesis of glycosyltransfer enzyme inhibitors. Other targets of current interest include the enzymes involved in viral infection (e.g. HIV protease, influenza neuraminidase), glycoprotein and glycolipid processing (e.g. glycosyltransferases, sulfotransferases, glycosidases), inflammatory development (e.g. leukotriene A4 hydrolase), metastasis, and the biosynthesis of bacterial cell walls.
Figure 2B. The multienzyme system involved in the synthesis of bacterial cell-wall peptidoglycan has been overexpressed and used in the synthesis of cell-wall glycopeptides and in the development of inhibitors targeting the glycosyltransfer reactions.(J. Am. Chem. Soc. (2001) 123, 9916). Bottom structure of transglycosylase (PNAS (2009) 106, 8824).
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