This proposal has been targeted at two areas of catalytic antibody research: The obtainment of new antibody catalysts and the development of new strategies for obtaining improved antibody catalysts, including antibodies with altered specificities and chemical reactivities. The development of new antibody catalysts will center around a hapten design strategy which we introduced and termed """"""""bait and switch"""""""" catalysis. We will apply this strategy for our investigation of antibodies which can catalyze cationic cyclization processes. We will explore two types of cationic cyclization reactions. The first involves antibody catalyzed olefin cyclization processes and thus the formation of carbon-carbon bonds. To augment these studies, we intend to also explore the possibility of utilizing antibody catalyzed cationic cyclization reactions to form carbon-heteroatom bonds. A long-term goal of these two projects is to channel this type of antibody catalysis for the formation of unique steroid and unusual heterocyclic molecules. An equally important reaction in the formation of carbon-carbon bonds is the Aldol condensation. Using our """"""""bait and switch"""""""" approach, we plan to investigate bimolecular antibody catalysis for an intermolecular Aldol reaction. We will engage a multisubstrate """"""""bait and switch"""""""" tact for the induction of amino acid residues in an antibody's combining site to act both as a Lewis acid catalyst and, to provide additional binding forces to overcome entropic loss which is seen when two substrates are brought together. An advantage of such catalytic antibodies would be the avoidance of environmentally damaging Lewis acids which are commonly employed in Aldol reactions. Hybridoma methodology has been used exclusively in the obtainment of catalytic antibodies. However, this process of isolating catalytic antibodies suffers from some limitations. Of special concern is the ability to generate a large enough array of monoclonal antibodies to screen for the desired activity. We intend to apply antibody phage display semisynthetic combinatorial libraries in conjunction with panning methodologies which are designed to select for antibody chemical catalysis. To complement these studies, we will also utilize antibody phage display methodologies to examine the potential of altering a catalytic antibody's specificity and chemical reactivity. This arsenal of antibody phage display studies which we have selected to investigate should provide us with a means to access more sophisticated modes of antibody catalysis.
