News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998
Catalytic Antibodies and the Application of Soluble Polymers in Organic
K.D. Janda, J.A. Ashley, T. Berg, O. Bruemmer, S. Chen, A. Datta, C. Gao,
D. Gravert, H. Han, C. Harwig, J. Hasserodt, T. Hoffman, D.M. Kubitz, C.-H. Lin,
C.-H. Lo, S. Mao, B. Metz,* G.P. McElhaney, N. Reed, J. Shaw, A. Simeonov, M.
Taylor, P. Wentworth, Jr., P. Wirsching, Y. Xie, X. Zhao, B. Zhou, R.A. Lerner
* Hoechst Marion Roussel, Inc., Cincinnati, OH
Hydrolysis of phosphodiester bonds, such as those found in DNA and RNA, is
a reaction of fundamental importance in living systems. Consequently, intense
efforts center on the development of novel phosphodiesterases for use in biochemistry
and medicine. Our approach is to exploit the diversity of the murine immune system
to generate antibodies with phosphodiesterase activity.
Specifically, we use a charged hapten that elicits a complementary charged
residue in the antibody-combining site during the evolutionary timescale of immunization.
This counter-charged residue then acts in a catalytic manner when the hapten
is "switched" to the substrate in question. Using this strategy, we designed
a hapten that generates the key features of general base catalysis used by RNase
A (Fig. 1). The rate of catalysis with several isolated catalytic antibodies
is only 2 orders of magnitude lower in proficiency than naturally occurring RNase
A. Because of these preliminary results, we envisage new hapten designs that
incorporate the salient features of both transition-state analog and charge complementarity
for the elicitation of antibodies with even more proficient RNase-like activity.
Polymer-supported synthesis of nonpeptide-nonnucleic acid molecules has been
growing at an exponential rate. Yet, adaptation of a series of complex reactions
from solution to solid-phase synthesis is still in early development. Indeed,
polymer-supported total synthesis of natural products has only recently been
successful. The prostaglandin family of natural products contains perhaps the
most physiologically potent nonprotein molecules found in mammals. Prostaglandins
play a vital role in inflammation, tissue repair, and the immune response. Their
complex structure and delicate framework have provided a benchmark for chemists
interested in demonstrating new synthetic strategies.
From a combinatorial standpoint, polymer-supported synthesis of such molecules
ushers in another degree of complexity to the synthetic scheme. Although screening
large numbers of such compounds would greatly improve the probability of finding
appropriate biological activity, we are using novel soluble polymers to synthesize
these complex molecules in a combinatorial format.
Our reasoning is based on ease of purification and flexibility of these supports
to adapt to a variety of chemical reactions. Figure 2 shows a prostaglandin E2 scaffold
that we used to synthesize a library of prostaglandin molecules on soluble polymer
supports. We anticipate that this library of prostanoid molecules will greatly
enhance screening efforts to elucidate new molecules of biological activity.
Berg, T., Vandersteen, A.M., Janda, K.D. High-throughput synthesis
and direct screening for the discovery of novel hydrolytic metal complexes. Bioorg.
Med. Chem. Lett. 8:1221, 1998.
Chen, S., Janda, K.D. Total synthesis of naturally occurring prostaglandin
F2α on a non-cross-linked polystyrene support. Tetrahedron Lett.
Gao, C., Lavey, B.J., Lo, C.-H.L., Datta, A., Wentworth, P., Jr., Janda,
K.D. Direct selection for catalysis from combinatorial antibody libraries
using a boronic acid probe: Primary amide bond hydrolysis. J. Am. Chem. Soc.
Gravert, D.J., Janda, K.D. Bifunctional initiators for free radical
polymerization of non-crosslinked block copolymers. Tetrahedron Lett. 39:1513,
Gravert, D.J., Janda, K.D. Organic reactions on soluble polymer supports
as an alternative methodology for combinatorial solid-phase synthesis. In: Biotechnology
International. Connor, T.H., Hairi, R.J. (Eds.). Universal Medical Press, San
Francisco, 1997, p. 169.
Gravert, D.J., Janda, K.D. Soluble polyethylene glycol supports for
liquid-phase combinatorial synthesis. Drugs Future 22:1147, 1997.
Gravert, D.J., Janda, K.D. Synthesis on soluble polymers: New reactions
and the construction of small molecules. Curr. Opin. Chem. Biol. 1:107, 1998.
Han, H., Yoon, J., Janda, K.D. An efficient asymmetric route to 2,3-diaminobutanoic
acids. J. Org. Chem. 63: 2045, 1998.
Han, H., Yoon, J., Janda, K.D. Investigations of azapeptides as mimetics
of leu-enkephalin. Bioorg. Med. Chem. Lett. 8:117, 1998.
Hasserodt, J., Janda, K.D. Syntheses of octahydroquinoline-N-oxides:
Haptens designed to elicit catalytic antibodies that control a terpenoid-like
cascade cyclization. Tetrahedron 53:11237, 1997.
Hasserodt, J., Lerner, R.A., Janda, K.D. Formation of bridge-methylated
decalins by antibody-catalyzed tandem cationic cyclization. J. Am. Chem. Soc.
Heine, A., Stura, E.A., Yli-Kauhaluoma, J.T., Gao, C., Deng, Q., Beno,
B.R., Houk, K.N., Janda, K.D., Wilson, I.A. An antibody exo-Diels-Alderase
inhibitor complex at 1.95-Å resolution. Science 279:1934, 1998.
Hori, M., Janda, K.D. A soluble polymer approach to the "fishing out" principle:
Synthesis and purification of ß-amino alcohols. J. Org. Chem. 63:889, 1998.
Lin, C.-H., Hoffman, T.S., Xie, Y., Wirsching, P., Janda, K.D. An
antibody transesterase derived from reactive immunization that utilizes a wide
variety of alcohol substrates. J. Chem. Soc. Chem. Commun. 1075, 1998.
Wentworth, P., Jr., Janda, K.D. Catalytic antibodies. Curr. Opin.
Chem. Biol. 2:138, 1998.
Wentworth, P., Jr., Janda, K.D. Synthesis of oxorhenium (V) and oxotechnetium
(V) complexes as inhibitors of ribonucleases and for the generation of catalytic
antibodies. Synlett 5:537, 1997.
Wentworth, P., Jr., Liu, Y., Wentworth, A.D., Fan, P., Foley, M.J., Janda,
K.D. A bait and switch hapten strategy generates catalytic antibodies for
phosphodiester hydrolysis. Proc. Natl. Acad. Sci. U.S.A. 95:5971, 1998.
Yli-Kauhaluoma, J.T., Harwig, C.W., Wentaorth, P., Jr., Janda, K.D. Unexpected
1,3-oxazolidine formation in the attempted oxidation of N-aryl-N-methyl
substituted ß-amino alcohols using pyridinium dichromate. Tetrahedron Lett.