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    Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine
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    Molecular Modeling and Biopharmaceutical Center and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States
    *Phone: 859-323-3943. Fax: 859-257-7585. E-mail: [email protected]
    *E-mail: [email protected]
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2016, 11, 8, 2186–2194
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    https://doi.org/10.1021/acschembio.6b00277
    Published May 25, 2016
    Copyright © 2016 American Chemical Society
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    Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine). Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long-term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for the development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in the environment.

    Copyright © 2016 American Chemical Society

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    20. Huimei Wei, Linyue Shang, Chang-Guo Zhan, Fang Zheng. Effects of Cebranopadol on Cocaine-induced Hyperactivity and Cocaine Pharmacokinetics in Rats. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-66250-z
    21. Ting Zhang, Huimei Wei, Jing Deng, Fang Zheng, Chang-Guo Zhan. Clinical potential of a rationally engineered enzyme for treatment of cocaine dependence: Long-lasting blocking of the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine. Neuropharmacology 2020, 176 , 108251. https://doi.org/10.1016/j.neuropharm.2020.108251
    22. Xirong Zheng, Xiabin Chen, Ting Zhang, Max Zhan, Chang-Guo Zhan, Fang Zheng. Catalytic activities of cocaine hydrolases against the most toxic cocaine metabolite norcocaethylene. Organic & Biomolecular Chemistry 2020, 18 (10) , 1968-1977. https://doi.org/10.1039/C9OB02762A
    23. S. M. Nurulain, A. Adem, S. Munir, R. Habib, S. Awan, F. Anwar, S. Batool. Butyrylcholinesterase in Substance Abuse: An Overview. Neurophysiology 2020, 52 (2) , 145-158. https://doi.org/10.1007/s11062-020-09864-3
    24. . Appendix B: Metabolism of Major Illicit Drugs. 2020, 571-625. https://doi.org/10.1002/9781119658016.app2
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    26. Xirong Zheng, Linyue Shang, Chang-Guo Zhan, Fang Zheng. In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice. Drug and Alcohol Dependence 2019, 204 , 107462. https://doi.org/10.1016/j.drugalcdep.2019.04.033
    27. Xirong Zheng, Ziyuan Zhou, Ting Zhang, Zhenyu Jin, Xiabin Chen, Jing Deng, Chang-Guo Zhan, Fang Zheng. Effectiveness of a Cocaine Hydrolase for Cocaine Toxicity Treatment in Male and Female Rats. The AAPS Journal 2018, 20 (1) https://doi.org/10.1208/s12248-017-0167-4
    28. Xiabin Chen, Xirong Zheng, Kai Ding, Ziyuan Zhou, Chang-Guo Zhan, Fang Zheng. A quantitative LC–MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood. Journal of Pharmaceutical and Biomedical Analysis 2017, 134 , 243-251. https://doi.org/10.1016/j.jpba.2016.11.024
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2016, 11, 8, 2186–2194
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschembio.6b00277
    Published May 25, 2016
    Copyright © 2016 American Chemical Society
    Request reuse permissions

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