Re-engineering Butyrylcholinesterase as a Cocaine Hydrolase

Sun, Hongliang; Pang, Yuan Ping; Lockridge, Oksana; Brimijoin, Stephen

doi:10.1124/mol.62.2.220

Cited by 134 publications

(173 citation statements)

References 26 publications

(33 reference statements)

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“…As described fully elsewhere, monomeric protein was expressed in Chinese hamster ovary cells and purified to near homogeneity (495%) using blue affinity and ion exchange chromatography. Each batch of enzyme was titrated by incubation for 24 h with varying amounts of the irreversible inhibitor, DFP, followed by determination of residual activity (Sun et al, 2002a). For control experiments that required permanently inactivated enzyme, aliquots of Albu-CocH were incubated for 24 h at room temperature with DFP, 10 À4 M, and then dialyzed overnight at 41C against 50 mM sodium phosphate buffer, pH 7.4.…”

Section: Drug Reagents and Enzymesmentioning

confidence: 99%

“…Our research began with molecular dynamics simulation and computer-based ligand docking to guide mutations (A328W/Y332A) that elevated the BChE rate constant for cocaine hydrolysis (k cat ) by a factor of 40 (Sun et al, 2001(Sun et al, , 2002a. The double mutant blocked cocaine-induced locomotor activity in mice, blunted pressor responses in rats, and reduced drug accumulation in brain tissue (Sun et al, 2002b;Gao and Brimijoin, 2004).…”

Section: Introductionmentioning

confidence: 99%

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A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

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125

167

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Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

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Section: Drug Reagents and Enzymesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

Self Cite

125

167

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“…37 , 38 Finally, groups using butyrylcholinesterase (BChE), 39 , 40 the major cocaine-metabolizing enzyme present in the plasma of humans and other mammals, have reported that intravenous pretreatment with either wildtype or genetically engineered BChE can mitigate the behavioral and physiological effects of cocaine and accelerate its metabolism. [41][42][43] The main drawback common to all of these protein-based approaches is that none acts directly within the CNS; thus, their success depends solely on peripheral contact between the enzyme or antibody with ingested cocaine.…”

Section: E581mentioning

confidence: 99%

“…43 There are an estimated >10 30 phages in the biosphere and since phage particles typically outnumber prokaryotic cells by approiximately 10-fold in environmental samples, phages probably constitute an absolute majority of organisms on our planet. In particular, fi lamentous bacteriophage can be produced at high titer in bacterial culture, making production simple and economical.…”

Section: Bacteriophage and Its Therapeutic Applicationmentioning

confidence: 99%

RETRACTED ARTICLE: Recent advances for the treatment of cocaine abuse: Central nervous system immunopharmacotherapy

Dickerson

Janda

2005

AAPS J

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A BSTRACTCocaine addiction continues to be a major health and societal problem in spite of governmental efforts devoted toward educating the public of the dangers of illicit drug use. A variety of pharmacotherapies and psychosocial programs have been proposed in an effort to provide a method for alleviation of the physical and psychological symptoms of cocaine abuse. Unfortunately, these methods have been met with limited success, illustrating a critical need for new effective approaches for the treatment of cocaine addiction. Recently an alternative cocaine abuse treatment strategy was proposed using intranasal administration of an engineered fi lamentous bacteriophage displaying cocaine-sequestering antibodies on its surface. These phage particles are an effective vector for CNS penetration and are capable of binding cocaine, thereby blocking its behavioral effects in a rodent model. The convergence of phage display and immunopharmacotherapy has allowed for an investigation of the effi cacy of protein-based therapeutics acting within the CNS on the effects of cocaine in animal models and has uncovered a new tool in the battle against cocaine addiction.

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“…On the other hand, the concentration of cocaine in acute overdose patients may exceed the serum antibody concentration. In this case, a therapy based on the administration of enzymes or catalytic antibodies that hydrolyze cocaine could be effective in reducing the plasma concentration of the drug (9,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). However, the only use of any of the cocaine esterases or catalytic antibodies would be in overdose cases.…”

Section: Pharmacokinetic-based Therapies For Cocaine Abusementioning

confidence: 99%

The Rhodococcus sp. Cocaine Esterase: A Bacterial Candidate for Novel Pharmacokinetic‐based Therapies for Cocaine Abuse

2003

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SummaryCocaine is a powerful central nervous stimulant and among the most abused of drugs. Despite decades of efforts, however, no effective pharmacological treatments are available against cocaine addiction or toxic effects. Classical receptor-antagonist therapeutic approaches have not yielded significant effects, although cocaine targets are well known, thus fostering development of alternative therapeutic strategies. Recent evidence indicates that a sensible approach for treatment of cocaine abuse could be to interfere with cocaine pharmacokinetics, i.e. by preventing the drug from reaching the receptors responsible for its biological effects. Administration of cocaine binding antibodies as well as catalytic antibodies and enzymes that hydrolyze cocaine represent potential alternative therapeutic approach(es). The discovery of the cocaine esterase from the strain MB1 of the bacterium Rhodococcus sp. (cocE) could be a major breakthrough in this field; cocE hydrolyzes cocaine faster than any known cocaine esterase and catalytic antibody. IUBMB Life, 55: 397-402, 2003 Keywords Rhodococcus sp. esterase; human plasma butyrylcholinesterase; human liver carboxylesterase-1; human liver carboxylesterase-2; cocaine binding antibodies; cocaine binding catalytic antibodies; cocaine metabolism.

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Re-engineering Butyrylcholinesterase as a Cocaine Hydrolase

Cited by 134 publications

References 26 publications

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

RETRACTED ARTICLE: Recent advances for the treatment of cocaine abuse: Central nervous system immunopharmacotherapy

The Rhodococcus sp. Cocaine Esterase: A Bacterial Candidate for Novel Pharmacokinetic‐based Therapies for Cocaine Abuse

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