Catalytic activities of a highly efficient cocaine hydrolase for hydrolysis of biologically active cocaine metabolites norcocaine and benzoylecgonine
Year: 2023
Type: article
Abstract: Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. It is recognized as a promising therapeutic strategy to accelerate cocaine metabolism which can convert cocaine to pharmacologically inactive metabolite(s) using an efficient cocaine-metabolizing enzyme. Our previous studies have successfully designed and discovered a highly efficient cocaine hydrolase, denoted as CocH5-Fc(M6), capable of rapidly hydrolyzing cocaine at the benzoyl ester moiety. In the present study, we determined the kinetic parameters of CocH5-Fc(M6) against norcocaine (kcat = 9,210 min-1, KM = 20.9 µM, and kcat/KM = 1.87 × 105 min-1 M-1) and benzoylecgonine (kcat = 158 min-1, KM = 286 µM, and kcat/KM = 5.5 × 105 min-1 M-1) for the first time. Further in vivo studies have demonstrated that CocH5-Fc(M6) can effectively accelerate clearance of not only cocaine, but also norcocaine (known as a cocaine metabolite which is more toxic than cocaine itself) and benzoylecgonine (known as an unfavorable long-lasting metabolite with some long-term toxicity concerns) in rats. Due to the desired high catalytic activity against norcocaine, CocH5-Fc(M6) is capable of quickly detoxifying both cocaine and its more toxic metabolite norcocaine after intraperitoneally administering lethal dose of 60 or 180 mg/kg cocaine. In addition, the ability of CocH5-Fc(M6) to accelerate clearance of benzoylecgonine should also be valuable for the use of CocH5-Fc(M6) in treatment of cocaine use disorder.
Source: Scientific Reports
Authors: Linyue Shang, Zhenyu Jin, Huimei Wei, Shawn Park, Chang-Guo Zhan, Fang Zheng
Institution: University of Kentucky
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,390
Awards: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse, Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse, G5330388222, Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment, Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse, Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders, Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment, Redesign of Butyrylcholinesterase for Cocaine Metabolism, G9000059500, G9000223770
OpenAlex ID: W4315702437