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Scientists at The Scripps Research Institute Devise New Technique to Catalyze Chemical Reactions

La Jolla, CA. December 15, 1995 Immunization is one of the most important techniques in medicine and has been largely unchanged for the past 200 years. Now, a radical change in the process is being reported by a team of scientists at The Scripps Research Institute (TSRI). The group has developed a new technique, called reactive immunization, that enables catalytic antibodies to bind covalently to antigens, allowing the catalysis of chemical reactions previously thought to be impossible and with potential implications for the production of chiral drugs and novel therapeutic agents. Catalytic antibodies are immune system proteins that not only bind to specific targets but also behave like catalysts, chemically rearranging them.

The technique, whereby antibodies catalyze the aldol reaction, an important carbon-carbon bond-forming reaction, was developed by TSRI President Richard A. Lerner, M.D., and members of the Department of Molecular Biology, Carlos F. Barbas, III, Ph.D., with postdoctoral fellow Jurgen Wagner. Lerner and Kim Janda, Ph.D., with TSRI colleagues Peter Wirsching, Jon A. Ashley, and Chih-Hung L. Lo, developed antibodies which catalyze ester hydrolysis. Two papers, on the development of the technology and production of the catalytic antibodies, appear in the December 15 issue of Science.

According to Barbas, "We believe that this technique ultimately will enable scientists to develop a better way to produce chiral drugs. The methodology obviates the need to employ a number of toxic solvents traditionally used to make these kinds of compounds."

Chirality, or "handedness," refers to molecules that exist in mirror-image versions -- right-handed or left-handed. The issue of chirality is especially critical in the pharmaceutical industry. While one "handed" version can be extremely safe and beneficial, its mirror image can yield devastating consequences.

Another potential application is the development of tight-binding antibodies made possible by covalent bonding. Janda comments, "Reactive immunization could eventually be useful medically to generate antibodies that would bind permanently to a target."

This is an important advance since the carbon-carbon bond forming reaction is one of the most widely used in making pharmaceuticals, other potential clinical applications include the development of antibiotics, chemotherapeutic agents, and diagnostic and imaging materials.

In general, antibodies bind non-covalently with their substrates. But reactive immunization allows for the production of antibodies that bind covalently, making it possible for them to catalyze reactions that were previously thought to be impossible. Lerner explains, "What we are trying to do is cause a chemical reaction to take place in the binding pocket of an antibody, because there are elements of that chemical reaction that will be later used in a catalytic event. The antibodies go forward and their progeny will make that covalent bond with a similar substrate. That covalent bond then becomes part of the catalytic event." Lerner continued that one-third of all natural enzymes work by covalent mechanisms.

The scientists used the technique to generate catalytic antibodies that catalyze the aldol reaction, one of the most important carbon-carbon bond-forming reactions in biology and chemistry. Their aim was to generate antibodies that are capable of catalyzing reactions with a greater range of substrates than the enzymes that exist in nature. Lerner says, "The natural catalysts are too highly restricted in the substrates they use to be of general use to chemists."

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