Rational design of an enzyme mutant for anti-cocaine therapeutics

Zheng, Fang; Chen, Zhan

doi:10.1007/s10822-007-9144-9

Cited by 31 publications

(28 citation statements)

References 49 publications

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“…Steven Brimijoin at the Mayo Clinic (46) and Chan-Guo Zhan of the University of Kentucky (47, 48) have developed an improved versions of HBC which can be administered as a biological treatment or delivered by a viral vector (49) to block the activity of cocaine by rapidly hydrolyzing cocaine in circulation. If this enzyme treatment were used together with anti-cocaine antibodies elicited by vaccination, a synergistic effect would be achieved, as the cocaine would be bound rapidly by the antibody on initial exposure, and then hydrolyzed as it is slowly released from an antibody, further reducing its potential access to the brain (50).…”

Section: Alternate Approaches For Anti-cocaine Vaccinesmentioning

confidence: 99%

Anti-cocaine vaccine development

Kinsey¹,

Kosten²,

Orson³

2010

Expert Review of Vaccines

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Cocaine abuse is an ongoing and serious problem which has lead to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed, and one has progressed to clinical trials. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction. KeywordsSubstance Abuse; Vaccination; Cocaine; Immunotherapy HistoryCocaine is one of the oldest known drugs. The leaves of the coca plant have been chewed by the indigenous peoples of South America for thousands of years to increase stamina for high altitude work and to afford feelings of well-being. In 1859, the active ingredient in coca was isolated and named cocaine, and it was considered a rather benign drug until the beginning of the 20 th century, when the negative aspects of its use became widely recognized (1). The sale and distribution of opium, coca leaves, and their derivatives was restricted in the United States under the 1914 Harrison Narcotics Tax Act to the practice of medicine, dentistry, and veterinary medicine. However, the law was not strictly enforced for cocaine, and there was open use of the drug for a number of years, although this was generally limited to the minority and low income urban populations, artists, and musicians (2). The addictive properties of cocaine were again gradually recognized, but in spite of this and increased efforts to enforce drug laws, the use of cocaine, particularly the smoked free base form known as crack, exploded during the 1970's and 80's. There is some light on the horizon, however, as data gathered by SAMSHA, the Substance Abuse and Mental Health Services Administration of the US Department of Health and Human Services shows that admissions to substance abuse treatment for cocaine decreased from 1995 to 2005, and the age of those admitted went up substantially (3). Even though there was a decrease in admissions among African-Americans, there was an increase Anti-drug VaccinesIt has been known and studied for at least 50 years that small molecules (haptens) will not usually elicit an immune response unless they are covalently attached to an immunogenic protein (6,7). This results in the body's tolerance for most medications and chemical exposures without significant harmful immune reactions. Allergic reactions to medicines like penicillin occur when the immune system recognizes the chemical or its metabolic products after they have been bound to native proteins, allowing for antigen presentation and initiation of the immune response (8). Therefore, to produce an anti-drug vaccine, the hapten is covalently attached to a foreign carrier prote...

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Section: Alternate Approaches For Anti-cocaine Vaccinesmentioning

confidence: 99%

Anti-cocaine vaccine development

Kinsey¹,

Kosten²,

Orson³

2010

Expert Review of Vaccines

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“…Although its physiologic function is not yet completely revealed, butyrylcholinesterase plays a role in the body's ability to metabolize cocaine. 1–4 Wild-type BChE has a low catalytic efficiency against naturally occurring (-)-cocaine. In our laboratory, by use of a novel, systematic computational design approach based on transition-state simulations and activation free energy calculations, BChE mutants with an ~2000-fold improved catalytic efficiency were designed and discovered, which were shown to be sufficient for use as an exogenous enzyme in rodents and primates to prevent (-)-cocaine reaching central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

Zheng

Zhan

Huang

et al. 2014

Bioorganic & Medicinal Chemistry

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Butyrylcholinesterase (BChE) has been an important protein used for development of anti-cocaine medication. Through computational design, BChE mutants with ~2000-fold improved catalytic efficiency against cocaine have been discovered in our lab. To study drug-enzyme interaction it is important to build mathematical model to predict molecular inhibitory activity against BChE. This report presents a neural network (NN) QSAR study, compared with multi-linear regression (MLR) and molecular docking, on a set of 93 small molecules that act as inhibitors of BChE by use of the inhibitory activities (pIC50 values) of the molecules as target values. The statistical results for the linear model built from docking generated energy descriptors were: r2 = 0.67, rmsd = 0.87, q2 = 0.65 and loormsd = 0.90; The statistical results for the ligand-based MLR model were: r2 = 0.89, rmsd = 0.51, q2 = 0.85 and loormsd = 0.58; the statistical results for the ligand-based NN model were the best: r2 = 0.95, rmsd = 0.33, q2 = 0.90 and loormsd = 0.48, demonstrating that the NN is powerful in analysis of a set of complicated data. As BChE is also an established drug target to develop new treatment for Alzheimer’s disease (AD). The developped QSAR models provide tools for rationalizing identification of potential BChE inhibitors or selection of compounds for synthesis in the discovery of novel effective inhibitors of BChE in the future.

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“…Nevertheless, we have developed novel computational strategies and protocols [21,22,23,24,25,26,27,28] for rational design of high-activity enzymes against a given substrate through virtual screening of transition states, leading to discovery of a set of BChE mutants, known as cocaine hydrolases (CocHs), with at least 1,000-fold improved catalytic efficiency against (−)-cocaine compared to wild-type BChE [29,30,31,32]. The first one of our reported (and patented) high-activity mutants of BChE, i.e .…”

Section: Introductionmentioning

confidence: 99%

Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (−)-cocaine

Xue

Hou

Yang

et al. 2013

Chemico-Biological Interactions

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It can be argued that an ideal anti-cocaine medication would be one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, wild-type BChE has a low catalytic efficiency against naturally occurring (−)cocaine. Interestingly, wild-type BChE has a much higher catalytic activity against unnatural (+)cocaine. According to available positron emission tomography (PET) imaging analysis using [11C](−)-cocaine and [11C](+)-cocaine tracers in human subjects, only [11C](−)-cocaine was observed in the brain, whereas no significant [11C](+)-cocaine signal was observed in the brain. The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (−)cocaine comparable to that of wild-type BChE against (+)-cocaine. Our recently designed A199S/F227A/S287G/A328W/Y332G mutant of human BChE has a considerably improved catalytic efficiency against (−)-cocaine and has been proven active in vivo. In the present study, we have characterized the catalytic activities of wild-type BChE and the A199S/F227A/S287G/A328W/Y332G mutant against both (+)- and (−)-cocaine at the same time under the same experimental conditions. Based on the obtained kinetic data, the A199S/F227A/S287G/A328W/Y332G mutant has a similarly high catalytic efficiency (kcat/KM) against (+)- and (−)-cocaine, and indeed has a catalytic efficiency (kcat/KM = 1.84×109 M−1 min−1) against (−)-cocaine comparable to that (kcat/KM = 1.37×109 M−1 min−1) of wild-type BChE against (+)-cocaine. Thus, the mutant may be used to effectively prevent (−)-cocaine from entering brain and producing physiological effects in the enzyme-based treatment of cocaine abuse.

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Rational design of an enzyme mutant for anti-cocaine therapeutics

Cited by 31 publications

References 49 publications

Anti-cocaine vaccine development

Anti-cocaine vaccine development

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (−)-cocaine

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