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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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