Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats

Chen, Xiabin; Zheng, Xirong; Zhou, Ziyuan; Chen, Zhan; Zheng, Fang

doi:10.1016/j.cbi.2016.05.003

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…Strategies to deliver degradative enzymes have also been proposed for cocaine use disorders, and research is ongoing to develop stable, long-lasting forms of cocaine-degrading enzymes, including cocaine esterase, cocaine hydrolase (148)(149)(150)(151), and butyrylcholinesterase (152). Preclinical evidence has shown that these fusion proteins increase cocaine's metabolism (153,154).…”

Section: Promising Pharmacological Targetsmentioning

confidence: 99%

Neuroscience of Addiction: Relevance to Prevention and Treatment

Volkow

Boyle

2018

AJP

205

110

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Addiction, the most severe form of substance use disorder, is a chronic brain disorder molded by strong biosocial factors that has devastating consequences to individuals and to society. Our understanding of substance use disorder has advanced significantly over the last 3 decades in part due to major progress in genetics and neuroscience research and to the development of new technologies, including tools to interrogate molecular changes in specific neuronal populations in animal models of substance use disorder, as well as brain imaging devices to assess brain function and neurochemistry in humans. These advances have illuminated the neurobiological processes through which biological and sociocultural factors contribute to resilience against or vulnerability for drug use and addiction. The delineation of the neurocircuitry disrupted in addiction, which includes circuits that mediate reward and motivation, executive control, and emotional processing, has given us an understanding of the aberrant behaviors displayed by addicted individuals and has provided new targets for treatment. Most prominent are the disruptions of an individual's ability to prioritize behaviors that result in long-term benefit over those that provide short-term rewards and the increasing difficulty exerting control over these behaviors even when associated with catastrophic consequences. These advances in our understanding of brain development and of the role of genes and environment on brain structure and function have built a foundation on which to develop more effective tools to prevent and treat substance use disorder.

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Section: Promising Pharmacological Targetsmentioning

confidence: 99%

Neuroscience of Addiction: Relevance to Prevention and Treatment

Volkow

Boyle

2018

AJP

205

110

View full text Add to dashboard Cite

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“…In addition, our most recently reported study demonstrated a novel protein form of E12–7 (or CocH3), denoted as CocH3-Fc or the catalytic antibody analog, which is an Fc-fused CocH3 dimer (CocH3-Fc) constructed by using CocH3 to replace the Fab region of human immunoglobulin G1. A single dose of CocH3-Fc significantly accelerated cocaine metabolism in rats after 20 days and, hence, blocked cocaine-induced physiological and toxic effects for a long period of time .…”

Section: Resultsmentioning

confidence: 99%

Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine

et al. 2016

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Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine, but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine) at all. Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long-term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in the pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis, but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in environment.

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“…The sample extraction method used in this study was established in our previous studies [14, 35]. Briefly, internal standard (IS) solution (0.1 µM for each IS) with a volume equal to that of the whole blood was added to each blood sample.…”

Section: Methodsmentioning

confidence: 99%

A quantitative LC–MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood

Chen

Zheng

Ding

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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As new metabolic pathways of cocaine were recently identified, a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. One-step solid phase extraction was used to extract all of the ten compounds and corresponding internal standards from blood samples. All compounds and internal standards extracted were separated on an Atlantis T3 (100Å, 3 µm, 2.1 mm × 150 mm I.D) column and detected in positive ion and high sensitivity mode with multiple reaction monitoring. This method was validated for its sensitivity, linearity, specificity, accuracy, precision, recovery, and stability. All of the ten compounds were quantifiable ranging from the lower limit of quantification (LLOQs) of ~10 nM (1.9–3.2 ng/ml) to ~1000 nM (190–320 ng/ml) without any interfering substance. Accuracy and precision were determined, and both of them were within the acceptance criteria of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The recovery was above 66.7% for all compounds. Stability tests demonstrated the stability of compounds under different storage conditions in whole blood samples. The method was successfully applied to a pharmacokinetic study with co-administration of cocaine and alcohol in rats.

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Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats

Cited by 10 publications

References 27 publications

Neuroscience of Addiction: Relevance to Prevention and Treatment

Neuroscience of Addiction: Relevance to Prevention and Treatment

Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine

A quantitative LC–MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood

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