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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.


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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