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      Nerve Agents, Cocaine
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Abuse of cocaine is an intractable social and medical problem, and treatment has resisted traditional pharmacological methods. Rather than simply reversing the toxic effects of cocaine, our collaborative cocaine research program is investigating the use of artificial enzymes to quickly degrade circulating cocaine to prevent or reduce toxic effects.

All of our artificial enzymes attack cocaine at the same position, producing two inactive byproducts.

Cocaine esterase

Cocaine esterase (CocE) is an enzyme produced by the bacterium Rhodococcus sp., which grows in the rhizosphere of coca plants in South America. The bacterium can use cocaine as its sole source of carbon and nitrogen, with CocE initiating metabolism of the cocaine (Bresler et al., Appl Environ Microbiol. 2000 66:904-8). The enzyme gene has been cloned and crystallized (Larsen et al., Nat Struct Biol. 2002 9:17-21), and our collaborative program (led by James Woods) has been testing the use of CocE for cocaine detoxification in mice and rats (Cooper et al., 2006). We are actively working on catalytic and structural improvements to the protein for enhanced in vivo activity.

Butyrylcholinesterase

Butyrylcholinesterase (hBChE) is a naturally occurring liver enzyme that degrades a variety of substrates, including (-) cocaine with low efficiency. Interestingly, the enzyme degrades the (+) cocaine enantiomer at very high efficiency, and this property was exploited by Chang-Guo Zhan to develop a mutant hBCHE that cleaves naturally occurring (-) cocaine at high efficiency (Zheng & Zhan, 2007). Further design improvements in hBChE are continuing, and we are also investigating in vivo use of this enzyme for cocaine detoxification.

Cocaine catalytic antibodies

By creating antibodies (Mabs) to transition-state analogues of cocaine, Donald Landry created novel Mab 15A10, which not only binds cocaine but acts as an enzyme to detoxify at the same position as CocE and BChE (Landry et al., 1993). Administration of Mab 15A10 dramatically increases the amount of cocaine necessary to produce convulsions and death in rats (Mets et al., 1998), and the antibody is an effective antagonist of the reinforcing effects of cocaine in rats (Mets et al., 1998; Baird et al., 2000). The catalytic antibody was crystallized in order to understand more about its active site, and to provide information for structure-based humanization for therapeutic evaluation (Larsen et al., 2004).