Cocaine abuse is a major medical and public health problem. There is still no FDA-approved anti-cocaine medication. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Enhancing cocaine metabolism by administration of human butyrylcholinesterase (BChE) is recognized as an efficient treatment strategy for cocaine overdose and addiction. However, the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)- cocaine is low (kcat = 4.1 min-1 and KM = 4.5 ?M). Nevertheless, we have recently designed and discovered a set of BChE mutants, known as cocaine hydrolases (CocHs), with >1,000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. In vivo evidences and clinical data for the first one of our discovered and patented CocHs have demonstrated that our discovered CocHs are promising candidates for development of an anti-cocaine medication. Our recently designed, discovered and patented CocHs are significantly more potent. Built on our success in rational design and discovery of the CocHs, the currently proposed investigation is focused on rational design, preparation, and preclinical testing of a novel type of long-lasting CocH entities, denoted as Fc-CocH, obtained from fusion of CocH with Fc portion of human antibody IgG1.
The specific aims are: (1) to design new molecular entities of Fc-CocH that potentially have not only a high catalytic efficiency against (-)-cocaine, but also a long biologicl half-life;(2) to prepare and test the designed Fc-CocHs for their in vitro activities;(3) to characterize the in vivo potency, pharmacokinetics, and immunogenicity of Fc-CocHs in rats and rhesus monkeys;(4) to evaluate the actual effects of the promising Fc-CocHs (identified in Aim 3) on the physiological and behavior responses of animals to cocaine by performing cardiovascular assays and self-administration assays in rhesus monkeys. Accomplishment of this proposed investigation will result in the identification and development of the best possible Fc-CocH entity that has not only a high in vivo potency in blocking physiological effects of cocaine, but also a long biological half- life without immunogenicity. The long-lasting Fc-CocH entity optimized in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for cocaine addiction treatment in humans.
Accelerating cocaine metabolism has been recognized as a promising treatment strategy for cocaine overdose and abuse. The long-lasting cocaine-metabolizing enzymes to be tested in this project are promising candidates for an efficient anti-cocaine medication.
|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|
|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|
|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|
|Yuan, Yaxia; Quizon, Pamela M; Sun, Wei-Lun et al. (2016) Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake. Sci Rep 6:27314|
Showing the most recent 10 out of 41 publications