In combination with previous studies that demonstrate CocE's effectiveness in rodent models, the new results suggest that CocE may be a good candidate for clinical treatment of cocaine toxicity.
The research was presented at the American Society for Pharmacology and Experimental Therapeutics annual meeting on April 25.
The difficulty in designing a therapy for cocaine toxicity stems from the drug’s complex mechanism of action. Cocaine can block multiple targets in the brain and body, which accounts for this drug’s cardiovascular and anesthetic effects, as well as its strong addictive properties. In addition, many of the metabolites of cocaine formed by the body (such as norcocaine and cocaethylene) have similar and sometimes stronger effects than cocaine itself.
Due to the myriad of action sites that would need to be blocked to eliminate the toxic physiological effects of cocaine and its by-products, the best strategy to treating toxicity from overdose is to directly eliminate the drug.
CocE is an enzyme originally isolated from a soil bacterium found around the roots of the coca plant, that can break down cocaine into the same metabolites as the natural human enzyme butyrylcholinesterase, only much more rapidly.
CocE, however, is naturally unstable at the normal body temperature of 37°C. To enhance the thermal stability of the enzyme, the investigators used a series of biochemical and computational approaches to modify the enzyme.
The thermally stable CocE was found to effectively degrade cocaine and two of cocaine’s active metabolites, norcocaine and cocaethylene, and not degrade benzoylecgonine, the metabolite used in urinalyses for recent cocaine use. The researchers also evaluated CocE’s ability to break down cocaine in the presence of drugs commonly co-abused with cocaine, and observed no reduction in CocE’s action in the presence of alcohol, nicotine, and morphine, among others.