Antibody catalysis

It has recently become possible to exploit the diversity and specificity of the humeral immune system to create immunoglobulins capable of catalysis. Generation and characterization of catalytic antibodies for three concerted chemical reactions in which carbon-carbon bonds are made or broken are briefly reviewed. The production of monoclonal antibodies with tailored catalytic properties is a promising new strategy for creating novel enzyme-like molecules able to speed chemical reactions (ref. 1). In this approach, first suggested by Jencks in 1969 (ref. 2), a stable analog of a reaction's rate limiting transition state is used as a hapten to elicit an immune response. If the design of the transition state analog is a good one, some fraction of the induced antibodies will possess the desired catalytic activity and can be identified through screening. Early attempts to generate efficient catalytic antibodies were largely unsuccessful (ref. 31, but progress in this field has been rapid since 1986 due to the availability of improved transition state mimics and monoclonal antibodies. A wide range of chemical reactions from hydrolytic transformations to pericyclic processes has now proved amenable to antibody catalysis (ref. 1). Catalytic antibodies, like enzymes, exhibit rate accelerations, substrate specificity, and regioand stereoselectivity (ref. 1). Significantly, the specificity and selectivity of these systems correlates precisely with the structure of the antigen used to elicit the immune response. These properties can therefore be set by the researcher through synthesis of an appropriate transitionstate analog. The ability to design at will highly efficient catalytic antibodies for any given reaction is likely to have far reaching consequences in both medicine and industry. Tailored antibody catalysts are potentially important as tools for studying how natural enzymes work, and as practical agents for accelerating reactions for which natural enzymes are unsuitable or unavailable. Because to their specificity and biocompatibility, they are also attractive candidates for applications in vivo. Concerted reactions in which carbon-carbon bonds are formed or broken are especially attractive targets for antibody catalysis, because they generally do not require the participation of catalytic general acids, general bases and nucleophiles which are difficult to introduce into the antibody combining site during immunization. For this reason, and as outlined below, we have selected several reactions for investigation that do not require chemical catalysis: a decarboxylation (ref. 4), a bimolecular Diels-Alder cycloaddition (ref. 5), and a Claisen rearrangement (ref. 6). These three transformations are of enormous importance in both biology and chemistry (including organic synthesis). In addition to their intrinsic chemical interest, concerted transformations of this sort have the potential to illuminate some of the elementary mechanisms by which proteins accelerate reactions. Specifically, they allow us to assess the roles of desolvation, proximity and strain in catalysis. A detailed understanding of these fundamental principles is essential if we hope to optimize the design of individual transition state analogs, improve the properties of our first-generation catalysts through mutagenesis, or expand the repertoire of reactions accelerated by antibodies.