Catalytic Antibodies

Irene Lee and Stephen J Benkovic, Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA

The concept of inducing antibodies that would possess, in addition to their exquisite ligand specificity, catalytic potential has its roots in the seminal contributions of Pauling. His proposal, that the ability of an enzyme to speed up a chemical reaction stemmed from the 'complementarity of the enzyme's active site structure to the activated complex', shifted the research focus from concerns about substrate-enzyme fit to a means for defining the structural requirements for binding the transition state. Since a transition state by definition has a negligible lifetime, evidence was sought for transition state stabilization in the tighter binding of inhibitors whose structures mimicked those of the presumed transition state relative to the weaker binding of substrate. Many examples of such high-affinity transition state inhibitors are now documented. However, stabilization of the transition state alone is necessary but not sufficient to give catalysis, which requires differential binding of substrate and transition state. The use of transition state analogs to induce catalytic antibodies successfully stems not only from this differential binding but other factors such as the introduction of catalytic residues. Nevertheless, it was apparent that such inhibitors would furnish a convenient starting point for creating catalytic antibodies which would owe their catalytic properties to their ability to bind the transition state of the reaction. Earlier attempts, however, were thwarted by the use of polyclonal rather than monoclonal antibodies, and by the need for better transition state mimics. In some cases, optimum haptens cannot be obtained owing to difficulties in the synthesis of precise mimics.

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