News and Publications
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).
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.
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,
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,
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.