Cocaine addiction continues to be a major health and social problem in the United States and other countries. Currently employed pharmacological agents for treating cocaine abuse have proved inadequate, leaving few treatment options. One alternative is to use protein-based therapeutics that bind cocaine, thereby blocking its effects, and/or degrade cocaine via hydrolysis of the benzoyl ester. This approach is especially attractive because the therapeutic agents exert no pharmacodynamic action of their own and therefore have little potential for side effects. The effectiveness of these agents, however, is limited by their inability to act directly within the central nervous system (CNS). We seek to address this deficiency by engineering filamentous bacteriophage, which have been shown to penetrate the CNS when administered intranasally, to display cocaine-sequestering proteins on its surface. Specifically, the aims of this proposal are: (1) construction of phagemid vectors that contain the genes of different cocaine-inactivating proteins as fusions with genes of phage coat proteins; (2) preparation and evaluation of phage displaying the various proteins of interest; (3) use of a locomotor activity rodent model to evaluate the ability of phage-displayed proteins to block the psychoactive effects of cocaine; (4) evaluation of phage distribution in the animals using immunohistochemical and molecular biological methods; (5) evaluation of a potential humoral immune response to the phage in the animals.
| Rogers, Claude J; Mee, Jenny M; Kaufmann, Gunnar F et al. (2005) Toward cocaine esterase therapeutics. J Am Chem Soc 127:10016-7 |
