Development of a truly effective anti-cocaine medication has been very challenging, particularly for treatment of cocaine overdose. There is still no FDA-approved anti-cocaine medication. Enhancing cocaine metabolism by administration of butyrylcholinesterase (BChE) has been recognized as a promising treatment strategy for cocaine abuse. However, the catalytic activity of this plasma enzyme is low against the naturally occurring (-) - cocaine. Our recent integrated computational-experimental effort has led to discovery of high-activity mutants of human BChE, known as cocaine hydrolases (CocHs), with >1,000-fold improved catalytic efficiency against cocaine compared to wild-type BChE. In vivo evidences indicate that our discovered CocHs are promising candidates for development of an anti-cocaine medication, especially for the overdose treatment. In this proposed project, we focus on the selection and optimization of the most promising CocH as a novel therapeutic candidate for cocaine overdose treatment through a combined use of various in silico, in vitro, and in vivo approaches.
The specific aims are: (1) To prepare and characterize the discovered CocHs in vitro for their catalytic activity and stability;(2) To characterize the CocHs in vivo for their potency, biological/circulatory half-lives, and immunogenicity by using the CocH materials prepared in Aim 1;(3) To design, prepare, and characterize new CocH entities that have not only a high in vivo potency, but also a higher thermal stability and a longer circulatory half-life without immunogenicity. Accomplishment of this proposed investigation will result in the identification and development of the most promising CocH entity that has a high in vivo potency in the protective and rescuing effects, a high stability, and a sufficiently long biological half-life without immunogenicity. The CocH entity optimized in this investigation is expected to be highly effective and safe as an exogenous enzyme for cocaine overdose treatment in humans.
Accelerating cocaine metabolism has been recognized as a promising treatment strategy for anti-cocaine medication. Accomplishment of the proposed investigation will result in the identification of reliable candidates of a novel enzyme therapy for cocaine overdose.
|Yuan, Yaxia; Zheng, Fang; Zhan, Chang-Guo (2018) Improved Prediction of Blood-Brain Barrier Permeability Through Machine Learning with Combined Use of Molecular Property-Based Descriptors and Fingerprints. AAPS J 20:54|
|Zhang, Ting; Zheng, Xirong; Kim, Kyungbo et al. (2018) Blocking drug activation as a therapeutic strategy to attenuate acute toxicity and physiological effects of heroin. Sci Rep 8:16762|
|Chen, Xiabin; Deng, Jing; Cui, Wenpeng et al. (2018) Development of Fc-Fused Cocaine Hydrolase for Cocaine Addiction Treatment: Catalytic and Pharmacokinetic Properties. AAPS J 20:53|
|Kim, Kyungbo; Yao, Jianzhuang; Jin, Zhenyu et al. (2018) Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine. Chem Biol Interact 293:107-114|
|Kim, Kyungbo; Zheng, Fang; Zhan, Chang-Guo (2018) Oligomerization and Catalytic Parameters of Human UDP-Glucuronosyltransferase 1A10: Expression and Characterization of the Recombinant Protein. Drug Metab Dispos 46:1446-1452|
|Zheng, Xirong; Zhou, Ziyuan; Zhang, Ting et al. (2017) Effectiveness of a Cocaine Hydrolase for Cocaine Toxicity Treatment in Male and Female Rats. AAPS J 20:3|
|Chen, Xiabin; Zheng, Xirong; Ding, Kai et al. (2017) A quantitative LC-MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood. J Pharm Biomed Anal 134:243-251|
|Zhang, Ting; Zheng, Xirong; Zhou, Ziyuan et al. (2017) Clinical Potential of an Enzyme-based Novel Therapy for Cocaine Overdose. Sci Rep 7:15303|
|Jin, Yafei; Huang, Xiaoqin; Papke, Roger L et al. (2017) Design, synthesis, and biological activity of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors. Bioorg Med Chem Lett 27:4350-4353|
|Chen, Xiabin; Zheng, Xirong; Zhou, Ziyuan et al. (2016) Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats. Chem Biol Interact 259:104-109|
Showing the most recent 10 out of 54 publications