Catalytic antibodies are still early in their development and are only now beginning to reveal their scope and potential for application. The foundation for the science has been the use of transition-state (TS) analogue designs, which we and others developed and will continue to expand. However, other powerful approaches have emerged from our laboratory that allow the catalysis of new reactions. In particular, we have recently focused on the use of """"""""bait and switch"""""""" strategies, metallochelates, reactive immunization (RI) and novel methods of selection from antibody libraries. We plan to invoke the """"""""bait and switch"""""""" paradigm to address the cationic cyclization of oxidosqualene derivatives to steroids. This would be a significant achievement and would aid in the understanding of the cyclase enzymes. Two """"""""bait and switch"""""""" designs, along with an oxorhenium metallochelate model, will be used to procure antibodies that cleave the phosphodiester bond. Our metallochelate approach has already shown success. Again, this is an important biological reaction in which antibody catalysts could be useful tools for study and application. In addition, we have used the bait and switch approach for addressing the amide hydrolysis problem. We have also embarked on exploring an area of research aimed at comparing the principle of TS stabilization with the concept of RI. We hope to begin to elucidate the major advantages of each approach. The emphasis herein is on application to hydrolytic kinetic resolutions. Finally, antibody libraries will be recruited to solve the problem of peptide bond hydrolysis. One approach will utilize our proven mechanism-based selection of combinatorial libraries. Importantly, the panning reagent can also be adapted to RI. A novel strategy will invoke catalytic screening of a mutant library derived from an existing catalytic antibody template. Consequently, we will attempt to convert an esterase into an amidase. Access to new tailor-made antibody catalysts would advance the field and shed light on enzyme mechanisms and evolution, and provide potentially valuable immunological reagents for use in medicine and industry.
