LARGE RATE ACCELERATIONS IN ANTIBODY CATALYSIS BY STRATEGIC USE OF HAPTENIC CHARGE

GENERAL acid-base catalysis contributes substantially to the efficacy of many enzymes, enabling an impressive array of eliminations, isomeri zations, racemizations, hydrolyses and carbon-carbon bond-forming reac tions to be carried out with high rates and selectivities(1). The fund amental challenge of exploiting similar effects in designed catalysts such as catalytic antibodies(2,3) is that of correctly positioning the catalytic groups in an appropriate active-site microenvironment, Char ge complementarity between antibody and hapten (the template used to i nduce an antibody) has been used successfully in a number of instances to elicit acids and bases within immunoglobulin combining sites(4-9), but the activities of the catalysts obtained by this strategy are gen erally considerably lower than those of natural enzymes, Here we repor t that by optimizing hapten design and efficiently screening the immun e response, antibodies can be obtained that act effectively as general base catalysts. Thus a cationic hapten correctly mimicking the transi tion-state geometry of all reacting bonds and bearing little resemblan ce to the reaction product has yielded carboxylate-containing antibodi es that catalyse an E2 elimination with more than 10(3) turnovers per active site and rate accelerations of greater than 10(8). These result s demonstrate that very large effects can be achieved by strategic use of haptenic charge.