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. |
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