News and Publications

Reaction Coordinate Manipulation and the Potential Treatment of Metabolic Disease Through Catalytic Antibodies

C. Shevlin, R. Lerner

By exploiting nature's own combinatorial system, it has been possible to elicit immunoglobulins that catalyze reactions that are difficult or impossible to carry out by other means. With this powerful tool at hand, it is reasonable to suggest that methods that use catalytic antibodies may be pivotal both in providing a tool to generate tailor-made catalysts and in managing a number of metabolic diseases.

REACTION COORDINATE MANIPULATION

One major focus of research in our laboratory is the development of antibody-assisted disfavored reactions. We have elicited immunoglobulins capable of catalyzing chemical reactions along an energetically unfavorable reaction pathway, providing an overwhelming enhancement of disfavored products relative to the uncatalyzed reaction.

Recently, we generated 2 new antibodies, 5C8 and 14D9, that catalyze the disfavored enantioselective 6-endo-tet closure of a -hydroxy epoxide. In collaboration with I. Wilson's group, Department of Molecular Biology, the crystal structures of both the native and the hapten-bound Fabs of 5C8 have been solved at 2.0 Å. We used information from this structure to elucidate a plausible reaction mechanism used by 5C8 to form a tetrahydropyran (3 in Fig. 1).

The ability to modulate the path taken by a substrate along its reaction coordinate through de novo catalyst design has inspired us to investigate other reaction types. One area that we are exploring is the use of catalytic antibodies to probe and manipulate the reaction pathway of carbocation rearrangements associated with the "memory effect." We anticipate that through judicious hapten design, an antibody binding pocket can be programmed that will alter the course of a substrate along the reaction coordinate so that an intermediate carbocation will rearrange via an alternative pathway, resulting in an inverse memory effect. Information gained from these investigations will provide insight into the still-unresolved basis of this phenomenon.

GAUCHER'S DISEASE

Gaucher's disease is one of several inborn errors of metabolism characterized by multisystem abnormalities, including degeneration of the skeletal system and enlargement of the liver and spleen. These effects are due to a deficiency in glucocerebrosidase that causes the accumulation of glucosylceramide in macrophages. Using the information obtained from the crystal structure of the 5C8 Fab, we have begun to synthesize new haptens designed to mimic the transition state for the cleavage of the glycosidic bond of glucosylceramide. Immunization with these hapten conjugates should elicit an immune response, resulting in the generation of antibodies with glucocerebrosidase activity. Because IgG can traverse the cell membrane of macrophages, antibodies with glucocerebrosidase activity may be clinically valuable in the treatment of Gaucher's disease. Design of systems for related disorders such as Fabrey's disease and Krabbe's disease is also being pursued.