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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999


Artificial Antibodies, Catalytic Antibodies, and Materials Tailored Specifically for Organic Synthesis


K.D. Janda, J.A. Ashley, O. Brümmer, R.A. Carrera, C.-W. Cho, A. Cordova, P. Garibay,* C. Gao, H. Han, C.W. Harwig, J. Hasserodt, T. Hoffman, L. Jones, G.-T. Kim, D.M. Kubitz, M. Kubitz, K.-J. Lee, C.-H. Lo, U.F. Mansoor, M. Matsushita, S. Mao, G.P. McElhaney, W.A. Metz,** J. Lopez-Pellegrin, N.N. Reed, F. Sieber, A. Simeonov, J.D. Toker, P. Toy, A.D. Wentworth, P. Wentworth, Jr., M. Wenz, P. Wirsching, B. Zeng, B. Zhou, R.A. Lerner

* Novo Nordisk A/S and The Royal Danish School of Pharmacy, Bagsvoerd, Denmark
** Hoechst Marion Roussel, Inc., Somerville, NJ

Phage display has been intensively investigated, yet many details of the phage particle itself have not been fully elucidated, and the possibility of alternative display formats has not been explored. The proteins III, VI, and VIII encoded by the phage genome have been used to display biological molecules, whereas those encoded by genes VII and IX have not. The proteins encoded by genes VII and IX are closely associated on the surface of filamentous bacteriophage opposite the end harboring the widely exploited gene III protein.

We developed a phagemid format in which the heavy- and light-chain variable regions of an antibody were fused to the amino termini of proteins encoded by gene VII and gene IX, respectively (Fig. 1).

Significantly, the fused proteins interacted to form a functional antibody domain on the phage surface. This result was the first time in which proteins encoded by genes VII and IX were harnessed for displaying an antibody or any protein on the phage surface. Our approach should be applicable to the display of generic peptides and protein libraries that can form combinatorial heterodimeric arrays. Consequently, the method is a major step toward the development of artificial antibodies and the selection of novel biological activities.

The first report of esterolytic catalytic antibodies in 1986 opened the door to use of these protein catalysts in the exploration of numerous chemical transformations. One reaction not yet associated with antibody catalysis is a 1,3-dipolar cycloaddition. We are exploring this reaction, which has wide application in chemical synthesis of biologically relevant compounds. Figure 2 details the reaction scheme and the haptenic structures we used to generate antibody catalysts. Besides obtaining a protein catalyst to a reaction that has not been observed in Nature, we also hope to address such issues as regioselective and enantioselective control and antibody microenvironment and entropic effects.

With the advent of combinatorial chemistry and automated synthesis, interest in polymer-supported reactions has been renewed. However, the polymer supports currently used for synthesis of products other than peptides or nucleotides are far from ideal. Determining new supports that are economically practical, have satisfactory physical characteristics, and are inert to a diverse range of reagents and catalysts commonly involved in a multistep combinatorial synthesis is not a trivial matter. We have prepared a new class of resins that meet the criteria stated (Fig. 3). The resins are based on a set of polytetrahydrofuran cross-linkers and are promising polymer supports for solid-phase synthesis and combinatorial chemistry.

Publications

Ashley, J.A., Lin, C.-H., Wirsching, P., Janda, K.D. Monitoring chemical warfare agents: A new method for the detection of methylphosphonic acid. Angew. Chem. Int. Ed. 38:1793, 1999.

Berg, T., Simeonov, A., Janda, K.D. A combined parallel synthesis and screening of macrocyclic lanthanide complexes for the cleavage of phospho di- and triesters and double-stranded DNA. J. Comb. Chem. 1:96, 1999.

Brümmer, O., Gao, C., Mao, S., Weiner, D.P., Janda, K.D. Design, synthesis and characterization of panning reagents for the selection of metalloantibodies. Lett. Pept. Sci. 6:295, 1999.

Gravert, D.J., Datta, A., Wentworth, P., Jr., Janda, K.D. Soluble supports tailored for organic synthesis: Parallel polymer synthesis via sequential normal/living free radical processes. J. Am. Chem. Soc. 120:9481, 1998.

Han, H., Yoon, J., Janda, K.D. Azatides as peptidomimetics: Solution and liquid phase syntheses. In: Peptidomimetics Protocols. Kazmierski, W.M. (Ed.). Humana Press, Totowa, NJ, 1999, p. 87. Methods in Molecular Medicine Series, Vol. 23.

Han, H., Cho, C.W., Janda, K.D. A substrate-based methodology that allows for the regioselective control of the catalytic aminohydroxylation reaction. Chem. Eur. J. 5:1565, 1999.

Harwig, C.W., Gravert, D.J., Janda, K.D. Soluble polymers: New options in both traditional and combinatorial synthesis. Chemtracts 12:1, 1999.

Hori, M., Gravert, D.J., Wentworth, P., Jr., Janda, K.D. Investigating highly cross-linked macroporous resins for solid-phase synthesis. Bioorg. Med. Chem. Lett. 8:2363, 1998.

Janda, K.D., Wentworth, A.D. A merging of chemistry and biology in terms of antibody catalysis. Phosphorus Sulfur Silicon Relat. Elem. 144:117, 1999.

Lerner, R.A., Barbas, C.F. III, Janda, K.D. Making enzymes. Harvey Lect. 92:1, 1998.

Paschall, C.M., Hasserodt, J., Jones, T., Lerner, R.A., Janda, K.D., Christianson, D.V. Convergence of catalytic antibody and terpene cyclase mechanisms: Polyene cyclization directed by carbocation-π interactions. Angew. Chem. Int. Ed. 38:1743, 1999.

Sieber, F., Wentworth, P., Jr., Toker, J.D., Wentworth, A.D., Metz, W.A., Reed, N.N., Janda, K.D. Development and application of a poly(ethylene glycol)-supported triarylphosphine reagent: Expanding the sphere of liquid-phase organic synthesis. J. Org. Chem. 64:5188, 1999.

Spivak, D.A., Hoffman, T.Z., Moore, A.H., Taylor, M.J., Janda, K.D. A comparison of flexible and constrained haptens in eliciting antibody catalysts for paraoxon hydrolysis. Bioorg. Med. Chem. 7:1145, 1999.

Taylor, M.J., Hoffman, T.Z., Yli-Kauhaluoma, J.T., Lerner, R.A., Janda, K.D. A light-activated antibody catalyst. J. Am. Chem. Soc. 120:12783, 1998.

Wentworth, P., Jr., Janda, K.D. Antibody catalysis of phosphodiester hydrolysis: A survey of hapten strategies. Phosphorus Sulfur Silicon Relat. Elem. 144:247, 1999.

Wentworth, P., Jr., Janda, K.D. Generating and analyzing combinatorial chemistry libraries. Curr. Opin. Biotechnol. 9:109, 1998.

Wentworth, P., Jr., Janda, K.D. Liquid-phase chemistry: Recent advances in soluble polymer-supported catalysts, reagents and synthesis. Chem. Commun. 19:1917, 1999.

Yoon, J., Cho, C.-W., Han, H., Janda, K.D. Solution and soluble polymer syntheses of 3-aminoimidazoline-2,4-diones. Chem. Commun. Issue 24:2703, 1998.

Zhao, X., Janda, K.D. Soluble polymer traceless linker investigations: Solvent effects on the desulfonylation of polyethylene glycol (PEG) substituted aryl alkyl sulfones with sodium amalgam. Bioorg. Med. Chem. Lett. 8:2439, 1998.

Zhao, X., Metz, W.A., Sieber, F., Janda, K.D. Expanding on the purification methodology of polyethylene glycol (PEG) bound molecules: The synthesis of 3,5-pyrazolidinediones. Tetrahedron Lett. 39:8433, 1998.

 

 







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