Suppression of psychoactive effects of cocaine by active immunization

Carrera, Marta; Ashley, Jon; Parsons, Loren H.; Wirsching, Peter; Koob, George F.; Janda, Kim D.

doi:10.1038/378727a0

Cited by 214 publications

(184 citation statements)

References 16 publications

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“…[1][2][3][4]6 An alternative approach is to interfere with the delivery of cocaine to its receptors or accelerate its metabolism in the body. 4,[7][8][9][10][11][12][13][14][15][16][17] Butyrylcholinesterase (BChE), the principal plasma enzyme that catalyzes cocaine hydrolysis into its biologically inactive metabolites, is an ideal target for this purpose. There are some clear advantages of using this enzyme to accelerate the cocaine metabolism.…”

Section: Introductionmentioning

confidence: 99%

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

et al. 2007

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A novel computational protocol based on free energy perturbation (FEP) simulations on both the free enzyme and transition state structures has been developed and tested to predict the mutation-caused shift of the free energy change from the free enzyme to the rate-determining transition state for human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The calculated shift, denoted by ΔΔG(1→2), of such kind of free energy change determines the catalytic efficiency (k cat /K M ) change caused by the simulated mutation transforming enzyme 1 to enzyme 2. By using the FEP-based computational protocol, the ΔΔG(1→2) values for the mutations A328W/Y332A → A328W/Y332G and A328W/Y332G → A328W/Y332G/A199S were calculated to be -0.22 and -1.94 kcal/mol, respectively. The calculated ΔΔG(1→2) values predict that the change from the A328W/Y332A mutant to the A328W/Y332G mutant should slightly improve the catalytic efficiency and that the change from the A328W/Y332G mutant to the A328W/Y332G/A199S mutant should significantly improve the catalytic efficiency of the enzyme for the (-)-cocaine hydrolysis. The predicted catalytic efficiency increases are supported by the experimental data showing that k cat /K M = 8.5 × 10 6 , 1.4 × 10 7 , and 7.2 × 10 7 min -1 M -1 for the A328W/Y332A, A328W/Y332G, and A328W/Y332G/A199S mutants, respectively. The qualitative agreement between the computational and experimental data suggests that the FEP simulations may provide a promising protocol for rational design of highactivity mutants of an enzyme. The general computational strategy of the FEP simulation on a transition state can be used to study the effects of a mutation on the activation free energy for any enzymatic reaction.

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Section: Introductionmentioning

confidence: 99%

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

et al. 2007

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“…For example, active immunization with a cocaine analog linked to keyhole limpet hemocyanin (KLH) significantly attenuated cocaine-induced psychomotor stimulation and sequestered cocaine in the periphery in rodents (Carrera et al, 1995(Carrera et al, , 2001. In addition, a KLHconjugated vaccine against cocaine prevented the reinstatement of responding for cocaine in rats, a rodent model of relapse to cocaine use (Carrera et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Several vaccines against cocaine have been in development, with one tested in clinical trials (Carrera et al, 1995;Haney and Kosten, 2004;Kosten et al, 2002;Orson et al, 2009). For example, active immunization with a cocaine analog linked to keyhole limpet hemocyanin (KLH) significantly attenuated cocaine-induced psychomotor stimulation and sequestered cocaine in the periphery in rodents (Carrera et al, 1995(Carrera et al, , 2001.…”

Section: Introductionmentioning

confidence: 99%

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

Wee

Hicks

et al. 2011

Neuropsychopharmacol

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Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3 H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (410 5 ) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

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“…Research has focused on immunization by cocaine binding antibodies (27)(28)(29)(30)(31)(32). Active or passive immunization with cocaine binding antibodies effectively reduces the effects of cocaine (28,29).…”

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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Suppression of psychoactive effects of cocaine by active immunization

Cited by 214 publications

References 16 publications

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

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

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