| Cocaine use is a widespread problem in the United States with 2 million current users who make about half a million emergency department visits each year. Although use is prevalent, there is currently no FDA-approved pharmacotherapy to specifically treat cocaine abuse or cocaine toxicity. Approaches toward developing therapies for these indications include small molecule inhibitors of cocaine binding and cocaine vaccines. These methods have proven to block the strong reinforcing properties of the drug; however, they do not prevent nor reverse cocaine's serious physiological effects. Our approach to treating cocaine toxicity and abuse is to rapidly hydrolyze the cocaine molecule into inactive metabolites using a bacterial cocaine esterase (CocE), thus eliminating cocaine's harmful and strong reinforcing effects.;This work has taken major steps toward developing CocE into a viable pharmacotherapy for both cocaine addiction and toxicity. Initially two thermostabilizing mutations were combined to improve the half-life of CocE. This mutant was pharmacologically characterized in vitro as well as in vivo using rodent models of cocaine lethality and reinforcement. The pharmacodynamic and pharmacokinetic properties of CocE, including in vivo rates of cocaine hydrolysis across species, circulating half-life, and mechanisms of elimination, were assessed. CocE's capacity to hydrolyze cocaine in the presence of commonly co-abused drugs, and its capacity to hydrolyze active cocaine metabolites were investigated. The results from these studies support the notion that cocaine esterase displays strong therapeutic potential, and that it may proceed towards clinical development. Moreover, it is a comprehensive analysis of how protein biologics may be used as effective pharmacotherapeutics. |
