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The Skaggs Institute
for Chemical Biology


Scientific Report 2006




Bioorganic Chemistry and Drug Discovery


C.-H. Wong, C. Bennett, A. Brik, S. Dean, S. Ficht, M. Fujio, W. Greenberg, R. Guy, S. Hanson, Z. Hong, T.-L. Hsu, D.-R. Hwang, J.-C. Lee, P.-H. Liang, L. Liu, R. Payne, T. Polat, M. Sawa, M. Sugiyama, D. Thayer, S.-K. Wang, L. Whalen, C.-Y. Wu, D. Wu, M. Wuchrer, Y.-Y. Yang

To provide better enzymes for organic synthesis, we have developed new enzymatic aldol reactions through directed evolution of aldolases and the use of borate as a mimic of phosphate. With this borate-mediated strategy, new syntheses of iminocyclitol derivatives as glycosidase inhibitors have been accomplished.

We have also designed and developed new substrates for fucosyltransferases and used the substrates as fluorescent glycoproteomic probes to study protein glycosylation in vivo. These methods will allow us to understand which protein, which fucosyltransferase, and which saccharide acceptor are involved in fucosylation and what roles these elements may play in cancer metastasis. This new imaging method enables us to monitor the processing of glycoproteins from the Golgi complex to the cell surface.

To study sugar-receptor interactions, we have developed new sugar arrays with cleavable linkers for direct mass spectrometry characterization and new aminoglycoside nanoparticles in combination with DNA arrays for the study of aminoglycoside-RNA binding specificity in a genome-wide manner.

In our effort to develop vaccines against HIV, influenza virus, and breast cancer, we have designed and synthesized new glycolipids as adjuvants. These glycolipids target CD1d, direct the sugar moiety to the receptor on natural killer T cells, and induce expression of cytokines, including IFN-γ and IL-4. We solved the structure of a CD1d-glycolipid complex, in collaboration with I.A. Wilson, the Skaggs Institute, and used the structure to design new glycolipids capable of selective IFN-γ induction for use as immunoadjuvants.

We have developed a new sugar-assisted glycopeptide ligation method that overcomes the need for an N-terminal cysteine residue, a requirement for traditional native chemical ligation methods. The sugar moiety contains a handle that delivers a thiol auxiliary and accelerates the ligation reaction. The sugar-assisted glycopeptide ligation will be useful for the synthesis of homogenous glycoproteins, which are important both for therapeutic applications and for structural and functional studies.

Publications

Brigl, M., van den Elzen, P., Chen, X., Meyers, J.H., Wu, D., Wong, C.-H., Reddington, F., Illarianov, P.A., Besra, G.S., Brenner, M.B., Gumperz, J.E. Conserved and heterogeneous lipid antigen specificities of CD1d-restricted NKT cell receptors. J. Immunol. 176:3625, 2006.

Brik, A., Ficht, S., Wong, C.-H. Strategies for the preparation of homogenous glycoproteins. Curr. Opin. Chem. 10:638, 2006.

Brik, A., Wu, C.-Y., Wong, C.-H. Microtiter plate based chemistry and in situ screening: a useful approach for enzymatic inhibitor discovery. Org. Biomol. Chem. 4:1446, 2006.

Brik, A., Yang, Y.-Y., Ficht, S., Wong, C.-H. Sugar-assisted glycopeptide ligation. J. Am. Chem. Soc. 128:5626, 2006.

Cheng, Y.-S.E., Lo, K.-H., Hsu, H.-H., Shao, Y.-M., Yang, W.-B., Lin, C.-H., Wong, C.-H. Screening for HIV protease inhibitors by protection against activity-mediated cytotoxicity in Escherichia coli. J. Virol. Methods 137:82, 2006.

Chuang, M.-H., Wu, M.-S., Lo, W.-L., Lin, J.-T., Wong, C.-H., Chiou, S.-H. The antioxidant protein alkylhydroperoxide reductase of Helicobacter pylori switches from a peroxide reductase to a molecular chaperone function. Proc. Natl. Acad. Sci. U. S. A. 103:2552, 2006.

Fujio, M., Wu, D., Garcia-Navarro, R., Ho, D.D., Tsuji, M., Wong, C.-H. Structure-based discovery of glycolipids for CD1d-mediated NKT cell activation: tuning the adjuvant versus immunosuppression activity. J. Am. Chem. Soc. 128:9022, 2006.

Hong, Z.-Y., Liu, L., Hsu, C.-C., Wong, C.-H. Three-step synthesis of sialic acids and derivatives. Angew. Chem. Int. Ed. 45:7417, 2006

Hsu, H.-Y., Hua, K.-F., Su, Y.-C., Chu, L.-C., Su, S.-C., Chiu, H.-W., Wong, C.-H., Chen, S.-T., Shieh, C.-W., Yang, S.-S., Chen, Y.-M., Chao, L.K. Alkali-soluble polysaccharides of Rhizoclonium riparium alga induce IL-1 gene expression via protein kinase signaling pathways. J. Agric. Food Chem. 54:3558, 2006.

Huang, C.-Y., Thayer, D.A., Chang, A.Y., Best, M.D., Hoffman, J., Head, S., Wong, C.-H. Carbohydrate microarray for profiling the antibodies interacting with Globo H tumor antigen. Proc. Natl. Acad. Sci. U. S. A. 103:15, 2006.

Huang, K.-T., Wu, B.-C., Lin, C.-C., Luo, S.-C., Chen, C., Wong, C.-H., Lin, C.-C. Multi-enzyme one-pot strategy for the synthesis of sialyl Lewis X-containing PSGL-1 glycopeptide. Carbohydr. Res., 341:2151, 2006.

Kinjo, Y., Tupin, E., Wu, D., Fujio, M., Garcia-Navarro, R., Benhnia, M.R.E.I., Zajonc, D.M., Ben-Menachem, G., Ainge, G.D., Painter, G.F., Khurana, A., Hoebe, K., Behar, S.M., Beutler, B., Wilson, I.A., Tsuji, M., Sellati, T.J., Wong,
C -H., Kronenberg, M.
Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat. Immunol. 7:978, 2006.

Lee, J.-C., Wu, C.-Y., Apon, J.V., Siuzdak, G., Wong, C.-H. Reactivity-based one-pot synthesis of tumor-associated antigen N3 minor octasaccharide for the development of a photocleavable DIOS-MS sugar array. Angew. Chem. Int. Ed. 45:2753, 2006.

Liang, F.-S., Brik, A., Lin, Y.-C., Elder, J.H., Wong, C.-H. Epoxide opening in water and screening in situ for rapid discovery of enzyme inhibitors in microtiter plates. Bioorg. Med. Chem. 14:1058, 2006.

Liang, F.-S., Greenberg, W.A., Hammond, J.A., Hoffmann, J., Head, S.R., Wong, C.-H. Evaluation of RNA-binding specificity of aminoglycosides with DNA microarrays. Proc. Natl. Acad. Sci. U. S. A. 103:12311, 2006.

Liang, P.-H., Cheng, W.-C., Lee, Y.-L., Yu, H.-P. Wu, Y.-T., Lin, Y.-L., Wong, C.-H. Novel five-membered iminocyclitol derivatives as selective and potent glycosidase inhibitors: new structures for antivirals and osteoarthritis. Chembiochem 7:165, 2006.

Lin, K.-I., Kao, Y.-Y., Kuo, H.-K., Yang, W.-B., Chou, A., Lin, H.-H., Yu, A.L-T., Wong, C.-H. Reishi polysaccharides induce immunoglobulin production through the TLR4/TLR2-mediated induction of transcription factor Blimp-1. J. Biol. Chem. 281:24111, 2006.

Lin, Y.-C., Brik, A., de Parseval, A., Tam, K., Torbett, B.E., Wong, C.-H., Elder, J.H. Altered gag polyprotein cleavage specificity of feline immunodeficiency virus/human immunodeficiency virus mutant proteases as demonstrated in a cell-based expression system. J. Virol. 80:7832, 2006.

Liu, H., Wong, C.-H. Characterization of a transglycosylase domain of Streptococcus pneumoniae PBP1b. Bioorg. Med. Chem. 14:7187, 2006.

Liu, L., Bennett, C.S., Wong, C.-H. Advances in glycoprotein synthesis. Chem. Commun. (Camb.) 21, 2006, Issue 1.

Liu, L., Hong, Z., Wong, C.-H. Convergent glycopeptide synthesis by traceless Staudinger ligation and enzymatic coupling. Chembiochem 7:429, 2006.

Qiul, H., Gabrielsen, A., Agardh, H.E., Wan, M., Wetterholm, A., Wong, C.-H., Hedin, U., Swedenborg, J., Hansson, G.K., Samuelsson, B., Paulsson-Berne, G., Haeggstrom, J.Z. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc. Natl. Acad. Sci. U. S. A. 103:8161, 2006.

Sanna, M.G., Wang, S.-K., Gonzalez-Cabrera, P.J., Don, A., Marsolais, D., Matheu, M.P., Wei, S.H., Parker, I., Jo, E., Cheng, W.-C., Cahalan, M.D., Wong, C.-H., Rosen, H. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat. Chem. Biol. 2:434, 2006.

Sawa, M., Hsu, T.-L., Itoh, T., Sugiyama, M., Hanson, S.R., Vogt, P.K., Wong, C.-H. Glycoproteomic probes for fluorescent imaging of fucosylated glycans in vivo. Proc. Natl. Acad. Sci. U. S. A. 103:12371, 2006.

Sawkar, A.R., Adamski-Werner, S.L., Cheng, W.-C., Wong, C.-H., Beutler, E., Zimmer, K.-P., Kelly, J.W. Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles. Chem. Biol. 12:1235, 2005.

Scanlan, C., Calarese, D., Lee, H.K., Blixt, O., Wong, C.-H., Wilson, I., Burton, D., Dwek, R., Rudd, P. Antibody recognition of a carbohydrate epitope: a template for HIV vaccine design,. Adv. Exp. Med. Biol. 564:7, 2005.

Thayer, D.A., Wong, C.-H. Vancomycin analogues containing monosaccharides exhibit improved antibiotic activity: a combined one-pot enzymatic glycosylation and chemical diversification strategy. Chem. Asian J. 1:445, 2006.

Whalen, L.J., Wong, C.-H. Enzymes in organic synthesis: aldolase-mediated synthesis of iminocyclitols and novel heterocycles. Aldrichim. Acta 39:63, 2006.

Wu, C.-Y., King, K.-Y., Kuo, C.-J., Fang, J.-M., Wu, Y.-T., Ho, M.-Y., Liao, C.-L., Shie, J.-J., Liang, P.-H., Wong, C.-H. Stable benzotriazole esters as mechanism-based inactivators of the severe acute respiratory syndrome 3CL protease. Chem. Biol. 13:261, 2006.

Wu, D., Zajonc, D.M., Fujio, M., Sullivan, B.A., Kinjo, Y., Kronenberg, M., Wilson, I.A., Wong, C.-H. Design of natural killer T cell activators: structure and function of a microbial glycosphingolipid bound to mouse CD1d. Proc. Natl. Acad. Sci. U. S. A. 103:3972, 2006.

Zajonc, D.M., Maricic, I., Wu, D., Halder, R., Roy, K., Wong, C.-H., Kumar, V., Wilson, I.A. Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J. Exp. Med. 202:1517, 2005.

 

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

Wong Web Site