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The Skaggs Institute
for Chemical Biology
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.
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