Our program aims to develop and exploit general strategies for preparing enzyme-like catalysts with tailored activities and specificities. Recent attention has focused on the mammalian immune system as a source of such molecules. Using the transition state analog approach enunciated by Jencks in 1969, we and others have generated antibody proteins that catalyze a wide variety of chemical transformations, including ester and amide hydrolysis, photochemical processes, a sigmatropic rearrangement, a elimination, and a Diels-Alder cycloaddition. In this proposal we seek to expand our program in this area and have specifically targeted catalysis of concerted chemical transformations, especially pericyclic processes and decarboxylations. These reactions do not require participation of active-site nucleophiles, general acids or general bases, but should be highly sensitive to strain and entropy considerations. The latter factors distinguish enzymes from ordinary chemical catalysts and are the principal effects that antibodies are likely to exploit in doing chemical work. Preparation and study of immunoglobulins that accelerate these processes efficiently will enhance our understanding of how natural enzymes achieve enormous rate enhancements and exacting selectivities. Further, pericyclic reactions are among the most important and versatile transformations available to synthetic chemists for constructing carbon-carbon bonds in complex natural products, therapeutic agents and synthetic materials of all kinds. The ability to catalyze these processes with the high rates and selectivities of enzymes will therefore have important consequences for practical applications of this technology in organic synthesis. The design of enzyme-like catalysts with tailored specificities also has far-reaching implications for medical research and the development of therapies related to cancer and other diseases. Within the foreseeable future, antibody catalysts may well be used as drugs that operate in vivo through catalysis to alter tumor metabolism or to destroy carcinogens and other toxins.
| Debler, Erik W; Müller, Roger; Hilvert, Donald et al. (2009) An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket. Proc Natl Acad Sci U S A 106:18539-44 |
| Debler, Erik W; Kaufmann, Gunnar F; Kirchdoerfer, Robert N et al. (2007) Crystal structures of a quorum-quenching antibody. J Mol Biol 368:1392-402 |
