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,
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
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.
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,
Duron, S.G., Polat, T., Wong, C.-H.
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,
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,
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,
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,
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,
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.