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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Bioorganic Chemistry and Biocatalysis


C.-H. Wong, G.-J. Shen, P.S. Sears, A.K. Datta, P. Alper, M. Burkart, S.-J. Chung, W. Greenberg, M. Hendrix, F. Huang, S.-C. Hung, C. Huwe, J. Jablonowski, K. Koeller, T. Lampe, V.-D. Le, T. Lee, C.-C. Lin, J. Liu, G. McGarvey, T. Machajewski, D. Manning, F. Moris-Varas, M. Mitchell, I. Ollmann, C. Rosenbohm, S. Priestley, A. Schleyer, O. Seitz, M. Shelton, E. Simanek, M. Smith, S. Takayama, V. Vassilev, K. Witte, R. Wischnat, T. Wittmann, X.-S. Ye, J. Yun, Z. Zhang

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 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 and chiral amine resolution and chemoenzymatic synthesis of glycopeptides and glycoproteins that involve the use of engineered subtilisins and recombinant glycosyltransferases in combination with solid-phase methods developed in this laboratory. We also developed a new method for the synthesis of 2-fluoroglycosides that uses Selectflour (Fig. 1).

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 (Fig. 2); viral proteases and RNA; and enzymes involved in the cell cycle, the processing of glycoproteins, and the transfer of the sulfate group. We developed new tight-binding inhibitors of certain viral and bacterial RNAs and of HIV proteases from drug-resistant mutants. We also discovered a new RNA-recognition motif based on cyclic 1,3-hydroxyamines and developed new sequence-specific RNA inhibitors that contain this motif as novel antibiotics (Fig. 3).

Publications

Alper, P., Hendrix, M., Wong, C.-H. Probing the specificity of aminoglycoside-RNA interactions with designed synthetic analogs. J. Am. Chem. Soc. 120:1965, 1998.

Hogg, J.H., Ollmann, I.R., Wetterhold, A., Andberg, M.B., Haeggstrom, J., Samuelsson, B., Wong, C.-H. Probing the activities and mechanisms of leukotriene A4 hydrolase using synthetic inhibitors and site-directed mutagenesis. Chem. Eur. J. 4:1698, 1998.

Jones, J.B., Wong, C.-H., Biocatalysis and biotransformation exploiting nature's magic. Curr. Opin. Chem. Biol. 2:67, 1998.

Kamitakahara, H., Suzuki, T., Nishigori, N., Suzuki, Y., Kanie, O., Wong, C.-H. Lyso-GM3 ganglioside-poly-l-glutamic acid conjugate as picomolar inhibitor of influenza hemagglutinin. Angew. Chem. Int. Ed. 37:1524, 1998.

Kanie, Y., Kirsch, A., Kanie, O., Wong, C.-H. Enzymatic assay of galactosyltransferase by capillary electrophoresis. Anal. Biochem. 263:240, 1998.

Lampe, T., Weitz-Schmidt, G., Wong, C.-H. Parallel synthesis of sialyl Lewis X mimetics on solid phase, a library approach toward fucopeptides. Angew. Chem. Int. Ed. 37:1707, 1998.

Lee, T., Laco, G.S., Torbett, B.E., Fox, H.S., Lerner, D.L., Elder, J.H., Wong, C.-H. Analysis of the S3 and S3´ subsite specificity of FIV protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV and HIV in vitro and ex vivo. Proc. Natl. Acad. Sci. U.S.A. 95:939, 1998.

Martin, R., Witte, K.L., Wong, C.-H. The synthesis and enzymatic incorporation of sialic acid derivatives for use as tools to study the structure, activity and inhibition of glycoproteins and other glycoconjugates. Bioorg. Med. Chem. 6:1283, 1998.

Miura, T., Kajimoto, T., Jimbo, M., Yamagishi, K., Inokuchi, J.-C., Wong, C.-H. Synthesis and evaluation of morpholino- and pyrrolidinosphingolipids as inhibitors of glycosylceramide synthase. Bioorg. Med. Chem. 6:1481, 1998.

Rosenthal, P.B., Zhang, X., Formanowski, F., Fitz, W., Wong, C.-H., Meier-Ewert, H., Skehel, J., Wiley, D.C. Three-dimensional structure of the haemagglutinin-esterase-function glycoprotein of influenza C virus. Nature 396:92, 1998.

Sears, P., Lin, C.-C., Hung, S.-C., Takayama, S., Witte, K.L., Alper, P.B., Wong, C.-H. Mechanism-based inhibition of carbohydrate-mediated biological recognitions. Chem. Commun. 11:1161, 1998.

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, in press.

Sears, P., Wong, C.-H. Enzyme action in glycoprotein processing. Cell. Mol. Life Sci. 54:223, 1998.

Simanek, E.E., Huang, D.-H., Seitz, O., Wong, C.-H. Glycosylation with ß-N-acetylglucosmine of threonine of the heptad repeat unit of RNA polymerase II stabilizes a reverse turn. J. Am. Chem. Soc. 45:11567, 1998.

Simanek, E., McGarvey, G.J., Wong, C.-H. Selectin-carbohydrate interaction: From natural ligands to designed mimics. Chem. Rev. 98:838, 1998.

Takayama, S., Lee, S.T., Hung, S.-C., Wong, C.-H. Designing acylating reagents for enzymatic resolution of amines. Chem. Commun., in press.

Takayama, S., McGarvey, G.J., Wong, C.-H. Enzymes in organic synthesis: Recent development in aldol reactions and glycosylations. Chem. Soc. Rev. 26:407, 1997.

Tsai, C.Y., Park, W.K.C., Weitz-Schmidt, G., Ernst, B., Wong, C.-H. Synthesis of sialyl Lewis X mimetics using the Ugi four-component reaction. Bioorg. Med. Chem. Lett. 8:2333, 1998.

Vassilev, V.P., Simanek, E.E., Wood, M.R., Wong, C.-H. Enzymatic synthesis of a chiral gelator with remarkably low molecular weight. Chem. Commun. 1865, 1998.

Wischnat, R., Martin, R., Wong, C.-H. Synthesis of a new class of N-linked Lewis X and LacnAc analogs as potential inhibitors of human fucosyltransferases: A general method for the incorporation of an iminocyclitor as transition-state mimic of the donor sugar to the acceptor. J. Org. Chem. 63:8361, 1998.

Witte, K., Seitz, O., Wong, C.-H. Solution and solid-phase synthesis of N-protected peptide esters of the benzyl type as substrates for subtilisin-catalyzed glycopeptide coupling. J. Am. Chem. Soc. 120:1979, 1998.

Wittmann, V., Takayama, S., Kong, K.W., Weitz-Schmidt, G., Wong, C.-H. Ligand recognition by E- and P-selectin: Chemoenzymatic synthesis and inhibitory activity of bivalent sialyl Lewis X derivatives and sialyl Lewis X carboxylic acids. J. Org. Chem. 63:5137, 1998.

Wong, C.-H., Hendrix, M., Manning, D.D. 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.

Wong, C.-H., Hendrix, M., Priestley, E.S., Greenberg, W.A. Specificity of aminoglycoside antibiotics for the ribosomal decoding region A-site RNA. Chem. Biol. 5:397, 1998.

Wong, C.-H., Ye, X.-S., Zhang, Z. Assembly of oligosaccharide libraries using a designed building block and an efficient orthogonal protection-deprotection strategy. J. Am. Chem. Soc. 120:7137, 1998.

 

 







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