The basic principle for the generation of catalytic antibodies was first proposed by Jencks and built on the precept of Pauling that the catalytic power of enzymes is derived, at least in part, from stabilization of the corresponding reaction's transition state. Therefore, isolation of a catalytic antibody involves, in its simplest form, probing the vast immune repertoire to elicit antibodies against a hapten that is a stable analog of the transition state of a reaction of interest. These antibodies, by nature of their programmed binding selectivity, should therefore lower the free energy of activation along the reaction coordinate, thereby catalyzing the process.
Over the last twenty years antibody catalysis has traversed many different paths. Throughout this time, we have pioneered various strategies beyond transition state analogues for eliciting catalytic antibodies including the "bait-and-switch" approach and "reactive immunization." Using of these strategies, antibodies have been isolated with have rate enhancements approaching those observed in natural enzymes. Furthermore, although the inception of the field in 1986 was based on catalysis of acyl transfer processes, it was quickly recognized that for antibodies to have significant impact within the organic community, chemical reactions that are disfavored or ones in which there are no enzyme counterparts would have to be investigated. We reported the first example of a disfavored chemical transformation catalyzed by an antibody in 1993, and have published numerous other examples of formally disfavored processes in the intervening years.
Using the principles described above, we have elicited antibody catalysts for a wide variety of reactions including ester hydrolysis and transesterification, amide hydrolysis, glycosidic bond hydrolysis, decarboxylations, anti-Baldwin ring closures, oxepane synthesis, the Diels Alder reaction, cationic cyclizations including tandem terpenoid cyclization processes, SN1 nucleophilic substitutions, cationic cyclopropanations, phosphate triester hydrolysis, peptidyl-prolyl isomerizations, 1,3-dipolar cycloadditions, syn elimination reactions, functionalization of dendrimers, metal-dependent acyl transfer processes, steroid isomerizations, the photo-Fries reaction, the synthesis of quinones from enediyne-containing molecules, blue-fluorescent antibodies, and the discovery that all antibodies, regardless of source or specificity, can produce oxidants including H2O2.
We continue to push the boundaries of what is believed possible using catalytic antibodies and remain a major contributor to this field as it continues to evolve. Examples of current projects in this area include harnessing the power of the intrinsic antibody oxidation potential for the catalytic degradation of biologically relevant molecules, design of novel haptens for elimination reactions relevant to drugs of abuse, and explorations of blue-fluorescent antibody technology in biological applications.
Catalytic Antibodies
