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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA035552-02
Application #
8636423
Study Section
Special Emphasis Panel (ZDA1-GXM-A (11))
Program Officer
Shih, Ming L
Project Start
2013-04-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$1,097,704
Indirect Cost
$272,090
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Zheng, Fang; Zhan, Chang-Guo (2016) Reply to Curry and Coombs: Benzoic acid is formed predominantly from the benzoyl ester hydrolysis in the presence of cocaine hydrolase. Proc Natl Acad Sci U S A 113:E2102-3
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
Zheng, Xirong; Deng, Jing; Zhang, Ting et al. (2016) Potential anti-obesity effects of a long-acting cocaine hydrolase. Chem Biol Interact 259:99-103
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
Zhang, Yuxin; Huang, Xiaoqin; Han, Keli et al. (2016) Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations. Chem Biol Interact 259:142-147
Wang, Guojun; Zhang, Ting; Huang, Haifeng et al. (2016) Plant expression of cocaine hydrolase-Fc fusion protein for treatment of cocaine abuse. BMC Biotechnol 16:72
Yao, Jianzhuang; Yuan, Yaxia; Zheng, Fang et al. (2016) Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of "hunger hormone" ghrelin. Sci Rep 6:22322
Chen, Xiabin; Xue, Liu; Hou, Shurong et al. (2016) Long-acting cocaine hydrolase for addiction therapy. Proc Natl Acad Sci U S A 113:422-7
Wei, Donghui; Tang, Mingsheng; Zhan, Chang-Guo (2015) Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA). Org Biomol Chem 13:6857-65
Chen, Xiabin; Huang, Xiaoqin; Geng, Liyi et al. (2015) Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase. Biochem J 466:243-51

Showing the most recent 10 out of 30 publications