It has recently become possible to exploit the diversity of the humeral immune system to create antibodies with tailored catalytic activities and specificities (i.e., abzymes). Because the properties of these catalysts are defined by the structure of the transition state analog that serves as the immunizing antigen, this technology provides a powerful and general method for preparing enzyme-like molecules on demand for practical applications in chemistry, biology and medicine. For example, the specificity and biocompatibility of immunoglobulin catalysts make them potentially attractive as agents for effecting vital chemical reactions in vivo. In order to investigate the feasibility of using abzymes to treat mammalian genetic diseases, two model systems will be investigated. Antibodies will be prepared that mimic the enzymes lipoprotein lipase and ornithine transcarbamoylase which play key roles in lipid and amino acid (arginine) metabolism, respectively. Operationally, the experimental approach to be followed has three steps. First, transition state analogs for the two acyl transfer reactions will be synthesized and used to generate antibodies. Second, the immune response to these compounds will be screened for efficient catalysts, the best of which will be characterized in chemical and structural detail. Third, the chemically most efficient abzymes will be evaluated in murine models of the two enzyme deficiencies. By targeting metabolic disorders caused by defective extra- and intracellular enzymes (lipoprotein lipase and ornithine transcarbamoylase, respectively) it will be possible to evaluate the efficacy of abzymes in both enzyme replacement and somatic gene therapies. The use of catalytic antibodies to treat mammalian diseases promises to be especially important in those cases where natural enzymes are unavailable, difficult to engineer, unstable, or otherwise unsuitable for therapeutic application. If successful, the proposed experiments will not only provide novel pharmacologically active proteins but also valuable tools for probing cellular metabolism and for dissecting the fundamental mechanisms by which proteins catalyze chemical reactions.
| Flohr, A; Aemissegger, A; Hilvert, D (1999) alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors. J Med Chem 42:2633-40 |
