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News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999
Bioorganic Chemistry
C.-H. Wong, G.-J. Shen, P.S. Sears, A.K. Datta, P. Alper, T. Baasov, M. Burkart,
S.-J. Chung, G. DeSantis, T. Flessner, S. Fong, W. Greenberg, H. Imagawa, M.
Izumi, F. Huang, K. Koeller, I. Koslov, K. Kreutter, V.-D. Le, T. Lee, C.-H.
Liang, C.-C. Lin, D. Lim, J. Liu, T. Machajewski, C.-C. Mak, D. Manning, M. Mitchell,
K. Niikura, I. Ollmann, T. Ritter, A. Romero, C. Rosenbohm, M. Smith, S. Sucheck,
M. Takayanagi, S. Takayama, F. Tian, T. Tolbert, C.-Y. Tsai, S. Vincent, K. Voss,
K. Witte, R. Wischnat, W.-G. Wu, Y. Xu, X.-S. Ye, Z. Zhang, H. Zhu
Our research programs focus on the development of new strategies for the study
and inhibition of important biological recognition processes. Our current interests
are directed toward (1) development of new chemoenzymatic strategies for the
synthesis of biologically active compounds and chiral intermediates, (2) combinatorial
and rational synthesis of inhibitors of enzymes and receptors, and (3) investigation
of reaction mechanisms.
Our work on chemoenzymatic organic synthesis includes the design of new substrates
and the exploitation of native, recombinant, and rationally modified enzymes
for organic synthesis. Our synthetic strategy emphasizes a combination of chemical
and enzymatic methods, with particular focus on the use of enzymes for stereocontrolled
processes. Our goal is to develop effective and environmentally friendly procedures
for the large-scale synthesis of biomedically important compounds.
In the past year, we developed several new synthetic methods. These included
novel enzymatic aldol addition reactions, chiral amine resolution, and chemoenzymatic
synthesis of glycopeptides (Fig. 1) and glycoproteins. We also developed a new
method for the synthesis of 2-fluoroglycosides that uses Selectfluor.
Our goals in enzyme and receptor inhibition are to develop new strategies
and discover new therapeutic agents that have high selectivity. Our efforts focus
on the design and synthesis of structure- or mechanism-based inhibitors of enzymes
or receptors associated with metabolic disorders or diseases. Current targets
for investigation include carbohydrate receptors; viral proteases and RNA (Fig.
2); and the enzymes involved in the cell cycle, the processing of glycoproteins,
and the transfer of sulfate groups. We developed new tight-binding inhibitors
of certain viral and bacterial RNAs and of HIV proteases from drug-resistant
mutants.
Publications
Burkart, M.D., Izumi, M., Wong, C.-H. Enzymatic regeneration of 3´-phosphoadenosine-5´-phosphosulfate
(PAPS) using aryl sulfotransferase: Synthesis of sulfated carbohydrates and spectrophotometric
assay of sulfotransferases. Angew. Chem. Int. Ed. 38:2747, 1999.
Burkart, M.D., Vincent, S.P., Wong, C.-H. An efficient synthesis of
CMP-3-fluoroneuraminic acid. Chem. Commun. 1525, 1999.
Burkart, M.D., Wong, C.-H. A continuous assay for the spectrophotometric
analysis of sulfotransferases using aryl sulfotransferase IV. Anal. Biochem.
274:131, 1999.
Chung, S.-J., Takayama, S., Wong, C.-H. Acceptor substrate-based selective
inhibition of galactosyltransferases. Bioorg. Med. Chem. Lett. 8:3359, 1998.
Depre, D., Duffels, A., Green, L.G., Lenz, R., Ley, S.V., Wong, C.-H. Synthesis
of glycans from the glycodelins: Two undeca-, two deca-, three nona-, an octa-
and a heptasaccharide. Chem. Eur. J. 5:3326, 1999.
Greenberg, W.A., Priestley, E.S., Sears, P.S., Alper, P.B., Rosenbohm,
C., Hung, S.-C., Wong, C.-H. Design and synthesis of new aminoglycoside antibiotics
using neamine as a core structure: Correlation of antibiotic activity with in
vitro inhibition of translation. J. Am. Chem. Soc. 121:6527, 1999.
Guo, C.-T., Wong, C.-H., Kajimoto, T., Miura, T., Ida, Y., Junega, L.R.,
Kim, M.J., Masuda, H., Suzuki, T., Suzuki, Y. Synthetic sialylphosphatidylethanolamine
derivatives bind to human influenza A viruses and inhibit viral infection. Glycoconj.
J. 15:1099, 1998.
Hendrix, M., Manning, D.D., Rosenbohm, C., Greenberg, W.A., Wong, C.-H. A
library approach to the discovery of small molecules that recognize RNA: Use
of a 1,3-hydroxyamine motif as core. J. Am. Chem. Soc. 120:8319, 1998.
Hiruma, K., Kanie, O., Wong, C.-H. Synthesis of analogs of 1,1-linked
galactosyl mannoside as mimetics of sialyl Lewisx tetrasaccharide.
Tetrahedron 54:15781, 1998.
Huwe, C.M., Woltering, T.J., Jiricek, J., Weitz-Schmidt, G., Wong, C.-H. Design,
synthesis and biological evaluation of aryl-substituted sialyl Lewisx mimetics
prepared via cross-metathesis of c-fucopeptides. Bioorg. Med. Chem. 7:425, 1999.
Kanemitsu, T., Kanie, O., Wong, C.-H. Quantitative monitoring of solid-phase
synthesis using gated decoupling 13C-NMR with 13C-enriched
protecting group and internal standard in the synthesis of sialyl Lewisx tetrasaccharide.
Angew. Chem. Int. Ed. 37:3415, 1998.
Kidd, R.D., Sears, P., Huang, D.-H., Witte, K., Wong, C.-H., Farber, G.K. Breaking
the low barrier hydrogen bond in a serine protease. Protein Sci. 8:410, 1999.
Lee, T., Le, V.-D., Lin, Y.-C., Wong, A.L., Morris, G.M., Olson, A.J.,
Elder, J.H., Wong, C.-H. Development of a new type of protease inhibitors
efficacious against FIV and HIV variants. J. Am. Chem. Soc. 121:1145, 1999.
Lin, C.-C., Moris-Varas, F., Weitz-Schmidt, G., Wong, C.-H. Synthesis
of sialyl Lewisx mimetics as selectin inhibitors by enzymatic aldol
condensation reactions. Bioorg. Med. Chem. 7:425, 1999.
Machajewski, T.D., Wong, C.-H. Chemoenzymatic synthesis of key epothilone
fragments. Synthesis S1:1469, 1999.
Mao, S., Gao, C., Lo, L., Wirsching, P., Wong, C.-H., Janda, K.D. Phage-display
library selection of high-affinity human single-chain antibodies to tumor-associated
carbohydrate antigens sialyl Lewisx and Lewisx. Proc. Natl.
Acad. Sci. U. S. A. 96:6953, 1999.
Sears, P., Witte, K., Wong, C.-H. The effect of counterion, water concentration,
and stirring on the stability of subtilisin BPN´ in organic solvents. J.
Mol. Catalysis 6:297, 1999.
Sears, P., Wong, C.-H. Carbohydrate mimetics: A new strategy for tackling
the problem of carbohydrate-mediated biological recognition. Angew. Chem. Int.
Ed. 38:2300, 1999.
Shen, G.-S., Datta, A.K., Izumi, M., Koeller, K.M., Wong, C.-H. Expression
of α2,8/2,9-polysialyltransferase from Escherichia coli K92: Characterization
of the enzyme and its reaction products. J. Biol. Chem. 274:35139, 1999.
Takayama, S., Chung, S.J., Igarashi, Y., Ichikawa, Y., Sepp, A., Lechler,
R.I., Wu, J., Hayashi, T., Siuzdak, G., Wong, C.-H. Selective inhibition
of ß-1,4- and α-1,3-galactosyltransferases: Donor sugar-nucleotide
based approach. Bioorg. Med. Chem. 7:401, 1999.
Takayama, S., Lee, S.T., Hung, S.-C., Wong, C.-H. Designing acylating
reagents for enzymatic resolution of amines. Chem. Commun. 127, 1999.
Takebayashi, M., Hiranuma, S., Kanie, Y., Kajimoto, T., Kanie, O., Wong,
C.-H. A versatile synthetic strategy for the preparation and discovery of
new iminocyclitols as inhibitors of glycosidases. J. Org. Chem. 64:5280, 1999.
Vincent, S., Burkart, M.D., Zhang, Z., Tsai, C.-Y., Wong, C.-H. Electrophilic
fluorination-nucleophilic addition reaction mediated by Selectfluor: Mechanistic
studies and new applications. J. Org. Chem. 64:5264, 1999.
Weitz-Schmidt, G., Gong, K.W., Wong, C.-H. Selectin/glycoconjugate
binding assays for the identification and optimization of selectin antagonists.
Anal. Biochem. 273:81, 1999.
Wischnat, R., Martin, R., Takayama, S., Wong, C.-H. Chemoenzymatic
synthesis of iminocyclitol derivatives: A useful library strategy for the development
of selective fucosyltransfer enzymes inhibitors. Bioorg. Med. Chem. Lett. 8:3353,
1998.
Witte, K., Skolnick, J., Wong, C.-H. A synthetic retrotransition (backwards
reading) sequence of the right handed three-helix bundle domain B (10-53) of
protein A shows similarity in conformation as predicted by computation. J. Am.
Chem. Soc. 120:13042, 1998.
Wong, C.-H. Mimics of complex carbohydrates recognized by receptors.
Accounts Chem. Res. 32:376, 1999.
Wu, W.-G., Pasternak, L., Huang, D.-H., Koeller, K.M., Lin, C.-C., Seitz,
O., Wong, C.-H. Structural study on O-glycopeptides: Glycosylation-induced
conformational changes of O-GlcNAc, O-LacNAc, O-sialyl-LacNAc and O-sialyl Lewisx peptides
of the mucin domain of MadCAM-1. J. Am. Chem.Soc., 121:2409, 1999.
Ye, Y.-S., Zhang, Z., Wong, C.-H. Assembly of oligosaccharide libraries
using a designed building block and an efficient orthogonal protection-deprotection
strategy. J. Am. Chem. Soc. 120:7137, 1998.
Yuasa, H., Hashimoto, H., Abe, Y., Kajimoto, T., Wong, C.-H. Studies
on the unusual stability of cis-2,5-diethoxy-1,4-dioxane-2,5-dimethanol.
Tetrahedron 55:2193, 1999.
Zhang, Z., Ollmann, I.R., Ye, X.-S., Wischnat, R., Baasov, T., Wong, C.-H. Programmable
one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 121:734, 1999.
Zhang, Z., Rosenthal, P.B., Fitz, W., Wong, C.-H., Meier-Ewert, H., Skehel,
J.J., Wiley, D.C. X-ray crystallographic determination of the structure of
the influenza C virus haemagglutinin-esterase-function glycoprotein. Acta Crystallogr.
D 55:945, 1999.
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