Cocaine Hydrolases Designed from Butyrylcholinesterase

Abstract

Accelerated cocaine metabolism producing biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway, i.e., cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma, is recognized as an ideal approach to therapeutic treatment of cocaine overdose and addiction. Unfortunately, the catalytic efficiency of wild-type BChE against naturally occurring, biologically active (−)-cocaine is too low to be effective. Unique computational enzyme redesign strategies and approaches have been developed and employed to rationally design and discover a variety of BChE mutants with at least 1,000-fold improved catalytic efficiency compared to the wild-type BChE against (−)-cocaine. These highly efficient mutants of BChE are recognized as the true CocHs. In vivo studies revealed that these CocHs were potent for accelerating cocaine metabolism, detoxifying cocaine, and eliminating abuse-related physiological effects of cocaine. Hence, these CocHs are promising therapeutic candidates for the treatment of cocaine overdose and addiction. In addition to their therapeutic potential for cocaine abuse, these CocHs may also be used as therapeutic agents for the treatment of aggression and obesity and as promising organophosphorus nerve agent bioscavengers. The first true CocH (i.e., CocH1) is currently under clinical trial phase II for cocaine addiction treatment. Compared to CocH1, the most recently designed and discovered CocH forms have not only significantly higher catalytic efficiency against (−)-cocaine but also significantly longer biological half-lives.