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News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000
Bioorganic Chemistry
G.-J. Shen, P.S. Sears, N. Braeur, M. Burkart, F. Burkhart, E. Chapman, G.
DeSantis, T. Flessner, S. Fong, W. Greenberg, F. Huang, S.-J. Huang, X. Huang,
H. Imagawa, M. Izumi, K. Koeller, I. Koslov, K. Kreutter, V.-D. Le, C.-H. Liang,
J. Liu, T. Machajewski, C.-C. Mak, M. Mitchell, K. Niikura, P. Nyffeler, T. Ritter,
A. Romero, R. Sadamoto, M. Silvestri, S. Sucheck, M. Takayanagi, F. Tian, T.
Tolbert, C.-Y. Tsai, S. Vincent, Y. Xu, X.-S. Ye, Z. Zhang, H. Zhu
Our research programs focus on the development of new strategies for the
study of important biological recognition processes. We are interested in 3 general
areas of research: (1) development of new and practical chemoenzymatic strategies
for the synthesis of biologically active compounds and chiral intermediates,
(2) design and synthesis of inhibitors that target RNA and enzymes, and (3) investigation
of reaction mechanisms.
In the past year, we developed several new chemoenzymatic synthetic methods.
Our ultimate goal is to develop effective and environmentally benign procedures
for the synthesis of complex biomolecules for biomolecule research. These procedures
include novel enzymatic aldol addition reactions and their application to the
synthesis of iminocyclitols and epothilones as potential anticancer agents, intein-mediated
synthesis of proteins containing carbohydrates and other molecular probes, and
chemoenzymatic synthesis of sulfated glycopeptides (Fig. 1).
In addition, we developed a computer-based method for the programmed synthesis
of oligosaccharides, which allows rapid assembly of oligosaccharides with minimal
manipulation of protecting groups. This new method is expected to facilitate
glycobiology research, and work is under way to use the method as a discovery
tool for the development of new aminoglycosides and oligosaccharides as candidates
for antibiotics and cancer vaccines. Our work on RNA led to the discovery of
bifunctional aminoglycosides that target bacterial RNA and at the same time inhibit
the bacterial enzymes that cause antibiotic resistance. This work also led to
the discovery of new aminoglycosides that target oncogenic RNA sequences (Fig.
2).
Publications
Burkart, M.D., Izumi, M., Chapman, E., Lin, C.-H., Wong, C.-H. Regeneration
of PAPS for the enzymatic synthesis of sulfated oligosaccharides. J. Org. Chem.
65:5565, 2000.
Fong, S., Machajewski, T.D., Mak, C.D., Wong, C.-H. Directed evolution
of d-2-keto-3-deoxy-6-phosphogluconate aldolase to new aldolases capable of making
d- and l-sugars. Chem. Biol. 7:873, 2000.
Hiranuma, S., Kanie, O., Wong, C.-H. Formation of the 1,2,6-orthoester
of mannose and its utilization in the glycosylation reaction. Tetrahedron Lett.
40:6423, 1999.
Koeller, K.M., Smith, M.E.B., Wong, C.-H. Chemoenzymatic synthesis
of PSGL-1 glycopeptides: Sulfation on tyrosine affects glycosyltransferase-catalyzed
synthesis of the O-glycan. Am. J. Chem. Soc. 122:4241, 2000.
Koeller, K.M., Smith, M.E.B., Wong, C.-H. Tyrosine sulfation on a
PSGL-1 glycopeptide influences the reactivity of glycosyltransferases responsible
for synthesis of the attached O-glycan. J. Am. Chem. Soc. 122:742, 2000.
Koeller, K.M., Wong, C.-H. Chemoenzymatic synthesis of sialyl-trimeric-Lewisx.
Chem. Eur. J. 6:1243, 2000.
Koeller, K.M., Wong, C.-H. Complex carbohydrate synthesis for glycobiologists:
Enzyme-based approach and programmable one-pot strategies. Glycobiology 10:1157,
2000.
Le, V.-D., Wong, C.-H. Synthesis of 2-substituted polyhydroxytetrahydropyrimidines
(N-hydroxy cyclic guanidino-sugars): Transition-state mimics of enzymatic
glycosidic cleavage. J. Org. Chem. 65:2399, 2000.
Li, M., Morris, G.M., Lee, T., Laco, G.S., Wong, C.-H., Olson, A.J., Elder,
J.H., Wlodawer, A., Gustchina, A. Structural studies of FIV and HIV-1 proteases
complexed with an efficient inhibitor of FIV protease. Proteins 38:29, 1999.
Machajewski, T.D., Wong, C.-H. The catalytic asymmetric aldol reaction.
Angew. Chem. Int. Ed. 39:1352, 2000.
Saotome, C., Kanie, Y., Kanie, O., Wong, C.-H. Synthesis and enzymatic
evaluation of five-membered iminocyclitols and a pseudodisaccharide. Bioorg.
Med. Chem. 8:2249, 2000.
Shibata, K., Hiruma, K., Kanie, O., Wong, C.-H. Synthesis of 1,1-linked
galactosyl mannosides carrying a thiazine ring as mimetics of sialyl Lewisx antigen:
Investigation of the effect of carboxyl group orientation on P-selectin inhibition.
J. Org. Chem. 65:2393, 2000.
Sucheck, S.J., Greenberg, W.A., Tolbert, T.J., Wong, C.-H. Design
of small molecules that recognize RNA: Development of aminoglycosides as potential
antitumor agents targeting oncogenic RNA sequences. Angew. Chem. Int. Ed. 39:1080,
2000.
Sucheck, S.J., Wong, A.L., Koeller, K.M., Boehr, D.D., Draker, K.-A.,
Sears, P., Wright, G.D., Wong, C.-H. Design of bifunctional antibiotics that
target bacterial rRNA and inhibit resistance-causing enzymes. J. Am. Chem. Soc.
122:5230, 2000.
Sun, X.-L., Kanie, Y., Guo, C.-T., Kanie, O., Suzuki, Y., Wong, C.-H. Syntheses
of C-3 modified sialylglycosides as selective inhibitors of influenza hemagglutinin
and neuraminidase. Eur. J. Org. Chem. 2643, 2000.
Takayanagi, M., Flessner, T., Wong, C.-H. A strategy for the solution-phase
parallel synthesis of N-(pyrrolidinylmethyl)hydroxamic acids. J. Org.
Chem. 65:3811, 2000.
Tolbert, T.J., Wong, C.-H. Intein-mediated synthesis of proteins containing
carbohydrates and other molecular probes. J. Am. Chem. Soc. 122:5241, 2000.
Vincent, S.P., Schleyer, A., Wong, C.-H. Asymmetric Strecker synthesis
of C-glycopeptide. J. Org. Chem. 65:4440, 2000.
Wittmann, V., Datta, A.K., Koeller, K.M., Wong, C.-H. Chemoenzymatic
synthesis and fluorescent visualization of cell-surface selectin-bound sialyl
Lewisx derivatives. Chem. Eur. J. 6:162, 2000.
Ye, X.-S., Wong, C.-H. Anomeric reactivity-based one-pot oligosaccharide
synthesis: A rapid route to oligosaccharide libraries. J. Org. Chem. 65:2410,
2000.
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