Abstract
Accelerating cocaine metabolism producing physiologically and biologically inactive metabolites is recognized as an ideal approach to therapeutic treatment of cocaine overdose and addiction. Butyrylcholinesterase (BChE) in plasma is the principal cocaine-metabolizing enzyme in humans. Unfortunately, catalytic efficiency of wild-type BChE against naturally occurring, biologically active (–)-cocaine is too low to be effective. Unique computational enzyme redesign approaches have been developed and employed to rationally design and discover a variety of BChE mutants, known as cocaine hydrolases (CocHs), with at least 1000-fold improved catalytic efficiency compared to the wild-type BChE against (–)-cocaine. Preclinical studies revealed that these CocHs are promising for treatment of cocaine overdose and addiction. The first CocH (i.e., CocH1) is currently under clinical trial phase II for cocaine addiction treatment. Compared to CocH1, more recently designed and discovered CocHs have not only significantly higher catalytic efficiency against (–)-cocaine and its toxic metabolites, but also significantly longer biological half-lives.
Published Version
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