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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA032910-03
Application #
8605871
Study Section
Special Emphasis Panel (ZDA1-JXR-D (06))
Program Officer
Shih, Ming L
Project Start
2012-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$610,225
Indirect Cost
$156,840
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
Yuan, Yaxia; Huang, Xiaoqin; Zhu, Jun et al. (2016) Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription. Future Med Chem :
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
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
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
Yao, Jianzhuang; Yuan, Yaxia; Zheng, Fang et al. (2016) Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of ""hunger hormone"" ghrelin. Sci Rep 6:22322
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
Yao, Yuan; Liu, Junjun; Zheng, Fang et al. (2016) Reaction Pathway for Cocaine Hydrolase-Catalyzed Hydrolysis of (+)-Cocaine. Theor Chem Acc 135:

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