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Scientific Report 2004


Chemistry




Bioorganic and Synthetic Chemistry


C.-H. Wong, F. Agnelli, C. Behrens, M. Best, A. Brik, M.C. Bryan, A. Chang, W.-C. Cheng, S. Duron, F. Fazio, D. Franke, C. Galan, Z.-Y. Hong, J. Hsu, C.-Y. Huang, F.-S. Liang, H.-K. Lee, L. Lee, H. Liu, J. Liu, M. Numa,P. Nyffeler, T. Polat, T. Ritter, D. Thayer, T. Tolbert, S.-K. Wang, G. Watt, D. Wu, Y.-Y. Yang, H. Yu, G.-W. Xing, R. Xu,/font>

Our research programs involve development of new chemical and enzymatic strategies and methods for the synthesis of biologically active compounds. We use the synthesized materials as molecular probes to explore carbohydrate-mediated biological recognitions, sequence-specific RNA recognition, and enzymatic reactions.

Organic And Bioorganic Synthesis

Our work in organic and bioorganic synthesis includes the development of new chemical reactions and the exploitation of native and engineered enzymes for organic synthesis. In the past year, we developed several new synthetic methods. These include use of sulfenyl amines and trific anhydride for glycosylation, use of aldolases in the synthesis of novel iminocyclitols for preparation of fucosyltransferase inhibitors, and synthesis of glycoproteins. Using directed evolution, we developed new aldolase variants capable of making D- and L-sugars. In collaboration with P.G. Schultz, Department of Chemistry, we also evolved an aminoacyl-tRNA synthase to accept O-linked glycosyl-amino acids for incorporation into proteins in vivo.

Development of Inhibitors of Enzymes and Receptors

Our goals in the area of enzyme and receptor inhibitors are to develop new strategies and discover potential new therapeutic agents with high selectivity. Current strategies involve the design and synthesis of structure- and mechanism-based inhibitors of enzymes associated with diseases. Targets for investigation include bacterial transglycosidase, sulfotransferases, retroviral proteases, the lethal factor of Bacillus anthracis, and the enzymes involved in the biosynthesis of carbohydrates essential for biological functions. We developed new iminocyclitols and derivatives as inhibitors of glycosidases and glycosyltransferases for potential treatment of inflammatory diseases. In addition, we used a new strategy based on a rapid microscale synthesis coupled with in situ high-throughput screening to develop new tight-binding inhibitors of anthrax lethal factor, a sulfotransferase, and drug-resistant HIV proteases. Finally, we designed and synthesized novel aminoglycoside mimetics that target unique bacterial and oncogenic RNA sequences as potential new antibiotics and anticancer agents.

Carbohydrate Chemistry and Molecular Glycobiology

We continued to improve the programmable 1-pot oligosaccharide synthesis method for convenient and rapid preparation of oligosaccharides. So far, we have designed approximately 600 building blocks and measured the anomeric reactivity of each building block. Using the computer program OptiMer, developed in our laboratory, we rapidly assembled a number of oligosaccharides. We are using this method to define the specificity of interactions between carbohydrates and their receptors, with particular emphasis on the optimization of the cancer antigen Globo H and gp120 oligomannose as vaccine candidates and development of aminoglycosides to target specific RNA sequences. In collaboration with D.R. Burton, Department of Immunology, and I.A. Wilson, Department of Molecular Biology, we are evaluating a designed oligomannose-protein conjugate as an antigen to elicit antibodies for neutralizing HIV gp120 and variants. We also prepared several heparin derivatives and glycoproteins for investigation of their structures and function. In collaboration with J.C. Paulson, Department of Molecular Biology, we developed new methods for microfabrication of saccharides in microtiter plates for use in the high-throughput analysis of sugar-protein interactions. We also developed new methods for discovery of enzyme inhibitors.

Publications

Agnelli, F., Sucheck, S.J., Marby, K.A., Rabuka, D., Yao, S.L., Sears, P.S., Liang, F.S., Wong, C.-H. Dimeric aminoglycosides as antibiotics. Angew Chem. Int. Ed. 43:1562, 2004.

Best, M.D., Brik, A., Chapman, E., Lee, L.V., Cheng, W.-C., Wong, C.-H. Rapid discovery of sulfotransferase inhibitors using diversity-oriented reactions in microplates followed by in situ screening. Chembiochem 5:811, 2004.

Brik, A., Muldoon, J., Lin, Y.-C., Elder, J.H., Goodsell, D.S., Olson, A.J., Fokin, V.V., Sharpless, K.B., Wong, C.-H. Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors. Chembiochem 4:1246, 2003.

Bryan, M.C., Wong, C.-H. Aminoglycoside array for the high-throughput analysis of small molecule-RNA interactions. Tetrahedron Lett. 45:3639, 2004.

Chapman, E., Best, M.D., Hanson, S.R., Wong, C.-H. Sulfotransferases: structure, mechanism, biological activity, inhibition, and synthetic utility. Angew. Chem. Int. Ed. 43:3526, 2004.

Chou, C.-H., Wu, C.-S., Chen, C.-H., Lu, L.-D., Kulkarni, S.S., Wong, C.-H., Hung, S.-C. Regioselective glycosylation of neamine core: a facile entry to kanamycin B related analogues. Org. Lett. 6:585, 2004.

Duron, S.G., Polat, T., Wong, C.-H. N-(phenylthio)-ε-caprolactam: a new promoter for the activation of thioglycosides. Org. Lett. 6:839, 2004.

Fazio, F., Bryan, M.C., Lee, H.-K., Chang, A., Wong, C.-H. Assembly of sugars on polystyrene plates: a new facile microarray fabrication technique. Tetrahedron Lett. 45:2689, 2004.

Fazio, F., Wong, C.-H. RuCl3-promoted amide formation from azides and thioacids. Tetrahedron Lett. 44:9083, 2003.

Feizi, T., Fazio, F., Chai, W., Wong, C.-H. Carbohydrate microassays: a new set of technologies at the frontier of glycomics. Curr. Opin. Struct. Biol. 13:637, 2003.

Franke, D., Machajewski, T., Hsu, C.-C., Wong, C.-H. One-pot synthesis of L-fructose using coupled multienzyme systems based on rhamnulose-1-phosphate aldolase. J. Org. Chem. 68:6828, 2003.

Hanson, S.R., Best, M.D., Wong, C.-H. Sulfatases: mechanism, biological activity, inhibition, and synthetic utility. Angew. Chem. Int. Ed., in press.

Heck, M.-P., Vincent, S.P., Murray, B.W., Bellamy, F., Wong, C.-H., Mioskowski, C. Cyclic amidine sugars as transition-state analogue inhibitors of glycosidases: potent competitive inhibitors of mannosidases. J. Am. Chem. Soc. 126:1971, 2004.

Lee, H.-K., Scanlan, C.N., Huang, C.-Y., Chang, A.Y., Calarese, D.A., Dwek, R.A., Rudd, P.M., Burton, D.R., Wilson, I.A., Wong, C.-H. Reactivity-based one-pot synthesis of oligomannoses: defining antigens recognized by 2G12, a broadly neutralizing anti-HIV-1 antibody. Angew. Chem. Int. Ed. 43:1000, 2004.

Lee, L.V., Bower, K.E., Liang, F.-S., Shi, J., Wu, D., Sucheck, S.J., Vogt, P.K., Wong, C.-H. Inhibition of the proteolytic activity of anthrax lethal factor by aminoglycosides. J. Am. Chem. Soc. 126:4774, 2004.

Lee, L.V., Mitchell, M.L., Huang, S.-J., Fokin, V.V., Sharpless, K.B., Wong, C.-H. A potent and highly selective inhibitor of human α-1,3-fucosyltransferase via click chemistry. J. Am. Chem. Soc. 125:9588, 2003.

Liu, J., Hsu, C.-C., Wong, C.-H. Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin. Tetrahedron Lett. 45:2439, 2004.

Mong, T.K.K., Lee, L.V., Brown, J.R., Esko, J.D., Wong, C.-H. Synthesis of N-acetyllactosamine derivatives with variation in the aglycon moiety for the study of inhibition of sialyl Lewis X expression. Chembiochem 4:835, 2003.

Ritter, T.K., Mong, K.-K.T., Liu, H., Nakatani, T., Wong, C.-H. A programmable one-pot oligosaccharide synthesis for diversifying the sugar domains of natural products: a case study of vancomycin. Angew. Chem. Int. Ed. 42:4657, 2003.

Wong, C.-H., Bryan, M.C. Sugar arrays in microtiter plates. Methods Enzymol. 362:218, 2003.

Wong, C.-H., Liang, F.S. Surface plasmon resonance study of RNA-aminoglycoside interaction. Methods Enzymol. 362:340, 2003.

Wu, C.-Y., Chang, C.-F., Chen, J.S.-Y., Wong, C.-H., Lin, C.-H. Rapid diversity-oriented synthesis in microtiter plates for in situ screening: discovery of potent and selective α-fucosidase inhibitors. Angew. Chem. Int. Ed. 42:4661, 2003.

Yu, H.N., Furukawa, J.-I., Ikeda, T., Wong, C.-H. Novel efficient routes to heparin monosaccharides and disaccharides achieved via regio- and stereoselective glycosidation. Org. Lett. 6:723, 2004.

Zhang, Z., Gildersleeve, J., Yang, Y.-Y., Xu, R., Loo, J.A., Urya, S., Wong, C.-H., Schultz, P.G. A new strategy for the synthesis of glycoproteins. Science 303:371, 2004.

 


Chi-Huey Wong, Ph.D.
Professor
Ernest W. Hahn Professor and Chair in Chemistry

Wong Web Site