A new approach is advanced which is aimed at expanding the scope of antibody catalysis. this entails the design of haptens which will elicit antibodies to catalyze acyl transfer reactions by a methodology which we term """"""""bait and switch"""""""" catalysis. What we propose involves the placement of a point charge on the hapten in close proximity to, or in direct substitution for, a chemical functional group we wish to transform in the respective substrate. The haptenic charge will induce a complementary charge (on an amino acid residue) at the binding site. The substrate will lack this charge, but will retain a similar overall structure. The monoclonal antibodies which bind these substrates now have the potential to act as general acids/bases for substrates having hydrolyzable functional groups. In addition, we intend to demonstrate how a multisubstrate intermediate analogue, having an appropriately positioned point charge, may induce antibodies to catalyze a bimolecular transmethylation reaction. Our ability to demonstrate the feasibility of these new strategies may eventually prove useful for the treatment of disease, as diagnostic reagents, or as industrial catalysts. The production of antibodies to catalyze various chemical reactions has proceeded at a fervent pace, while the general application of these catalytic antibodies to biomedical/biotechnological problems have lagged. By utilizing proven techniques and methodologies (transition state theory), we plan to obtain catalytic antibodies for use in areas of drug detoxification, peptide hydrolysis, and peptide coupling reactions. Finally we plan to pursue a detailed investigation on the mechanisms of antibody catalysis. We have obtained antibodies which catalyze ester and amide hydrolysis from haptens based on magnitude of the observed rate enhancements. By performing substrate specificity and kinetic studies we hope to rationalize these results and possibly expose some general principle which are applicable to these catalysis.
