Our research programs are directed toward (1) development of new chemical-enzymatic strategies for the synthesis of biologically active compounds and chiralintermediates, (2) rational modification of enzyme stability, specificity and specific activity, (3) design and synthesis of mechanism-based inhibitors of enzymes or receptors, (4) development of new enzymatic catalysts for organic reactions, and (5) investigation of reaction mechanisms.
ENZYME DEVELOPMENT AND ORGANIC SYNTHESIS. Our programs in this area include the development of novel substrates for existing enzymes and the exploitation of native, recombinant, or rationally modified enzymes for organic synthesis. Our synthetic strategy emphasizes a combination of chemical and enzymatic methods, with particular focus on the use of enzymes for stereocontrolled processes. Major efforts in synthetic carbohydrate chemistry include asymmetric aldol condensations for the synthesis of novel monosaccharides based on aldolases, and stereocontrolled synthesis of oligosaccharides and glycopeptides based on glycosyl transferases. Cloning and overexpression of these enzymes and the alteration of their substrate specificity are under way as part of our goals to develop new chemical-enzymatic strategies for practical synthesis of sugar-related substances. Site-directed mutagenesis and mechanism-based modification of proteases to peptide ligases for condensation of peptide and glycopeptide segments containing natural and unnatural amino acids have been developed and usd in the synthesis of homogeneous glycoproteins. We also are pursuing the development of new enzymatic methods for the synthesis of chiral synthons, designed molecules, and natural products of biomedical importance, and the discovery of new enzymes for new reactions.
DESIGN AND SYNTHESIS OF ENZYME OR RECEPTOR INHIBITORS. Our goals in this area are to develop new therapeutic agents with high selectivity. 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. Various azasugars 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. We are also developing carbohydrate mimetics as inhibitors of selectins and aminoglycoside mimetics as sequence-specific inhibitors of bacterial RNA.