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Enzyme-Based Cocaine Pharmacotherapies: Current Status and Projections for the Future

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Book cover Biologics to Treat Substance Use Disorders

Abstract

Cocaine abuse presents two issues on which pharmacotherapy should focus, viz., acute toxicity and chronic abuse. Treatment of acute toxicity requires an intervention with a very fast onset; duration of action is less critical. On the other hand, treatment of chronic abuse is feasible only with a very long-acting intervention. Research and development of two distinct types of anti-cocaine enzyme-based therapies, one bacterial and the other mammalian, are currently ongoing. A bacteria-based enzyme with pharmacokinetics appropriate for treatment of acute toxicity has been synthesized (cocaine esterase – CocE) and a derivative of it has reached clinical trial status. A mammalian-derived enzyme (cocaine hydrolase – CocH) with a half-life of two to three days is also in clinical trials for treatment of cocaine abuse; it remains to be seen whether this duration of action is sufficiently long to make this enzyme useful for most cocaine abusers. Pharmacological and behavioral procedures for evaluation of compounds of interest exist at both the preclinical and clinical levels. Discovery technology is making great strides toward the development of long-lasting enzyme therapeutics.

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Abbreviations

Albu-CocH:

Albumin-tagged cocaine hydrolase

CocE:

Cocaine esterase

CocH:

Cocaine hydrolase

PBS:

Phosphate-buffered saline

DM CocE:

Double mutant cocaine esterase

PEG CCRQ CocE:

Pegylated CocE with the dimer tightly bound

MDMA:

Methylenedioxymethamphetamine

References

  • Anker JJ, Brimijoin S, Gao Y, Geng L, Zlebnik NE, Parks RJ, Carroll ME. Cocaine hydrolase encoded in viral vector blocks the reinstatement of cocaine seeking in rats for 6 months. Biol Psychiatry. 2012;71:700–5.

    Article  CAS  PubMed  Google Scholar 

  • Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology. 2013;38(13):2698–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bresler MM, Rosser SJ, Basran A, Bruce NC. Gene cloning and nucleotide sequencing and properties of a cocaine esterase from Rhodococcus sp. strain MB1. Appl Environ Microbiol. 2000;66:904–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brim RL, Noon KR, Collins GT, Nichols J, Narasimhan D, Sunahara RK, Woods JH. The ability of bacterial cocaine esterase to hydrolyze cocaine metabolites and their simultaneous quantification using high-performance liquid chromatography-tandem mass spectrometry. Mol Pharmacol. 2011a;80:1119–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brim RL, Noon KR, Nichols J, Narasimhan D, Woods JH, Sunahara RK. Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs. Drug Alcohol Depend. 2011b;119:224–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brim RL, Noon KR, Collins GT, Stein A, Nichols J, Narasimhan D, Ko M-C, Woods JH, Sunahara RK. The fate of bacterial cocaine esterase (CocE), an in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination. J Pharmacol Exp Ther. 2012;340:83–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brim RL, Nance MR, Youngstrom DW, Narasimhan D, Zhan CG, Tesmer JJ, Sunahara RK, Woods JH. A thermally stable form of bacterial cocaine esterase: a potential therapeutic agent for treatment of cocaine abuse. Mol Pharmacol. 2010;77:593–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brimijoin S, Gao Y, Anker JJ, Gliddon LA, Lafleur D, Shah R, Zhao Q, Singh M, Carroll ME. A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats. Neuropsychopharmacology. 2008;33:2715–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brimijoin S, Orson F, Kosten TR, Kinsey B, Shen XY, White SJ, Gao Y. Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice. Chem Biol Interact. 2013;203:212–6.

    Article  CAS  PubMed  Google Scholar 

  • Carroll ME, Gao Y, Brimijoin S, Anker JJ. Effects of cocaine hydrolase on cocaine self-administration under a PR schedule and during extended access (escalation) in rats. Psychopharmacology (Berl). 2011;213:817–29.

    Article  CAS  Google Scholar 

  • Carroll ME, Zlebnik NE, Anker JJ, Kosten TR, Orson FM, Shen X, Kinsey B, Parks RJ, Gao Y, Brimijoin S. Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion. PLoS One. 2012;7(8):e43536. doi:10.1371/journal.pone.0043536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins GT, Zaks ME, Cunningham AR, St Clair C, Nichols J, Narasimhan D, Ko M-C, Sunahara RK, Woods JH. Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats. Drug Alcohol Depend. 2011;118:158–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins GT, Brim RL, Noon KR, Narasimhan D, Lukacs NW, Sunahara RK, Woods JH, Ko M-C. Repeated administration of a mutant cocaine esterase, effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys. J Pharmacol Exp Ther. 2012;342:205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins GT, Brim RL, Narasimhan D, Ko MC, Sunahara RK, Zhan CG, Woods JH. Cocaine esterase prevents cocaine-induced toxicity and the ongoing intravenous self-administration of cocaine in rats. J Pharmacol Exp Ther. 2009;331:445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cooper ZD, Narasimhan D, Sunahara RK, Mierzejewski P, Jutkiewicz EM, Larsen NA, Wilson IA, Landry DW, Woods JH. Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase. Mol Pharmacol. 2006;70:1885–91.

    Article  CAS  PubMed  Google Scholar 

  • Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Logan J, Bendriem B, Gatley SJ, Christman D. Mapping cocaine binding sites in human and baboon brain in vivo. Synapse. 1989;4:371–7.

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Atanasova E, Sui N, Pancook JD, Watkins JD, Brimijoin S. Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats. Mol Pharmacol. 2005;67:204–11.

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Brimijoin S. Lasting reduction of cocaine action in neostriatum – a hydrolase gene therapy approach. J Pharmacol Exp Ther. 2009;330:449–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Geng L, Orson F, Kinsey B, Kosten TR, Shen X, Brimijoin S. Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage. Chem Biol Interact. 2013;20:208–11.

    Article  Google Scholar 

  • Gao Y, LaFleur D, Shah R, Zhao Q, Singh M, Brimijoin S. An albumin-butyrylcholinesterase for cocaine toxicity and addiction: catalytic and pharmacokinetic properties. Chem Biol Interact. 2008;175:83–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao D, Narasimhan DL, Macdonald J, Brim R, Ko M-C, Landry DW, Woods JH, Sunahara RK, Zhan CG. Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol Pharmacol. 2009;75:318–23.

    Article  CAS  PubMed  Google Scholar 

  • Geng L, Gao Y, Chen X, Hou S, Zhan C-G, Radic Z, Parks RJ, Russell SJ, Pham L, Brimijoin S. Gene transfer of mutant mouse cholinesterase provides high lifetime expression and reduced cocaine responses with no evident toxicity. PLoS One. 2013;8(6):e67446. doi:10.1371/journal.pone.0067446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamza A, Cho H, Tai H-H, Zhan C-G. Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants. J Phys Chem B. 2005;109:4776–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heidbreder C. Rationale in support of the use of selective dopamine D3 receptor antagonists for the pharmacotherapeutic management of substance use disorders. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:167–76.

    Article  CAS  PubMed  Google Scholar 

  • Howell L, Nye J, Stehouwer J, Voll R, Mun J, Narasimhan D, Nichols J, Sunahara R, Goodman M, Carroll I, Woods JH. A mutant bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates. 2013.

    Google Scholar 

  • Huang X, Zhao X, Zheng F, Zhan C-G. Cocaine esterase-cocaine binding process and the free energy profiles by molecular dynamics and potential of mean force simulations. J Phys Chem B. 2012;116:3361–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol Rev. 1989;41:3–52.

    CAS  PubMed  Google Scholar 

  • Jutkiewicz EM, Baladi MG, Cooper ZD, Narasimhan D, Sunahara RK, Woods JH. A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality. Ann Emerg Med. 2009;54:409–20.

    Article  PubMed  Google Scholar 

  • Kirby KC, Carpenedo CM, Dugosh KL, Rosenwasser BJ, Benishek LA, Janik A, Keashen R, Bresani E, Silverman K. Randomized clinical trial examining duration of voucher-based reinforcement therapy for cocaine abstinence. Drug Alcohol Depend. 2013;132(3):639–45.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ko M-C, Narasimhan D, Berlin AA, Lukacs NW, Sunahara RK, Woods JH. Effects of cocaine esterase following its repeated administration with cocaine in mice. Drug Alcohol Depend. 2009;101:202–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko M-C, Bowen LD, Narasimhan D, Berlin AA, Lukacs NW, Sunahara RK, Cooper ZD, Woods JH. Cocaine esterase: interactions with cocaine and immune responses in mice. J Pharmacol Exp Ther. 2007;320:926–33.

    Article  CAS  PubMed  Google Scholar 

  • Landry DW, Zhao K, Yang GX, Glickman M, Georgiadis TM. Antibody-catalyzed degradation of cocaine. Science. 1993;259:1899–901.

    Article  CAS  PubMed  Google Scholar 

  • Larrimore KE, Barcus M, Kannan L, Gao Y, Zhan C-G, Brimijoin S, Mor T. Gene transfer of mutant mouse cholinesterase provides high lifetime expression and reduced cocaine responses with no evident toxicity. PLoS One. 2013;8(6):e67446. doi:10.1371/journal.pone.0067446.

    Article  Google Scholar 

  • Larsen NA, Turner JM, Stevens J, Rosser SJ, Basran A, Lerner RA, Bruce NC, Wilson IA. Crystal structure of a bacterial cocaine esterase. Nat Struct Biol. 2002;9:17–21.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Hamza A, Zhan C-G. Fundamental reaction mechanism and free energy profile for (−)-cocaine hydrolysis catalyzed by cocaine esterase. J Am Chem Soc. 2009;131:11964–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P, Gibler WB, Ohman EM, Drew B, Philippides G, Newby LK. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117:1897–907.

    Article  PubMed  Google Scholar 

  • Meredith TC, Mamat U, Kaczynski Z, Lindner B, Holst O, Woodard RW. Modification of lipopolysaccharide with colanic acid (M-antigen) repeats in Escherichia coli. J Biol Chem. 2007;282:7790–8.

    Article  CAS  PubMed  Google Scholar 

  • Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe RJ, Almonte R, Woods JH, Landry DW. A catalytic antibody against cocaine prevents cocaine’s reinforcing and toxic effects in rats. Proc Natl Acad Sci U S A. 1998;95:10176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narasimhan D, Nance MR, Gao D, Ko M-C, Macdonald J, Tamburi P, Yoon D, Landry DM, Woods JH, Zhan CG, Tesmer JJ, Sunahara RK. Structural analysis of thermostabilizing mutations of cocaine esterase. Protein Eng Des Sel. 2010;23:537–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narasimhan D, Collins GT, Nance MR, Nichols J, Edwald E, Chan J, Ko M-C, Woods JH, Tesmer JJ, Sunahara RK. Subunit stabilization and polyethylene glycolation of cocaine esterase improves in vivo residence time. Mol Pharmacol. 2011;80:1056–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newman AH, Blaylock BL, Nader MA, Bergman J, Sibley DR, Skolnick P. Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol. 2012;84:882–90.

    Article  CAS  PubMed  Google Scholar 

  • Pan Y, Gao D, Yang W, Cho H, Yang G, Tai HH, Zhan C-G. Computational redesign of human butyrylcholinesterase for anticocaine medication. Proc Natl Acad Sci U S A. 2005;102:16656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan Y, Gao D, Yang W, Cho H, Zhan C-G. Free energy perturbation (FEP) simulation on the transition-states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants. J Am Chem Soc. 2007;129:13537–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierce RC, O’Brien CP, Kenny PJ, Vanderschuren LJ. Rational development of addiction pharmacotherapies: successes, failures, and prospects. Cold Spring Harb Perspect Med. 2012;2(6):a012880.

    PubMed  Google Scholar 

  • Schindler CW, Justinova Z, Lafleur D, Woods D, Roschke V, Hallak H, Sklair-Tavron L, Redhi GH, Yasar S, Bergman J, Goldberg SR. Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. Addict Biol. 2013;18:30–9.

    Article  CAS  PubMed  Google Scholar 

  • Secades-Villa R, García-Rodríguez O, García-Fernández G, Sánchez-Hervás E, Fernandez-Hermida JR, Higgins ST. Community reinforcement approach plus vouchers among cocaine-dependent outpatients: twelve-month outcomes. Psychol Addict Behav. 2011;25:174–9.

    Article  PubMed  Google Scholar 

  • Sun H, Shen ML, Pang YP, Lockridge O, Brimijoin S. Cocaine metabolism accelerated by a re-engineered human butyrylcholinesterase. J Pharmacol Exp Ther. 2002;302:710–6.

    Article  CAS  PubMed  Google Scholar 

  • Turner JM, Larsen NA, Basran A, Barbas 3rd CF, Bruce NC, Wilson IA, Lerner RA. Biochemical characterization and structural analysis of a highly proficient cocaine esterase. Biochemistry. 2002;41:12297–307.

    Article  CAS  PubMed  Google Scholar 

  • Wood SK, Narasimhan D, Cooper Z, Sunahara RK, Woods JH. Prevention and reversal by cocaine esterase of cocaine-induced cardiovascular effects in rats. Drug Alcohol Depend. 2010;106:219–29.

    Article  CAS  PubMed  Google Scholar 

  • Xue L, Hou S, Tong M, Fang L, Chen X, Jin Z, Tai HH, Zheng F, Zhan C-G. Preparation and in vivo characterization of a cocaine hydrolase engineered from human butyrylcholinesterase for metabolizing cocaine. Biochem J. 2013;453:447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue L, Ko M-C, Tong M, Yang W, Hou S, Fang L, Liu J, Zheng F, Woods JH, Tai HH, Zhan C-G. Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine. Mol Pharmacol. 2011;79:290–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Xue L, Fang L, Chen X, Zhan C-G. Characterization of a high-activity mutant of human butyrylcholinesterase against (−)-cocaine. Chem Biol Interact. 2010;187:148–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Pan Y, Zheng F, Cho H, Tai H-H, Zhan C-G. Free-energy perturbation simulation on transition states and redesign of butyrylcholinesterase. Biophys J. 2009;96:1931–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhan C-G, Gao D. Catalytic mechanism and energy barriers for butyrylcholinesterase-catalyzed hydrolysis of cocaine. Biophys J. 2005;89:3863–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhan C-G, Zheng F, Landry DW. Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase. J Am Chem Soc. 2003;125:2462–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng F, Yang W, Xue L, Hou S, Liu J, Zhan CG. Design of high-activity mutants of human butyrylcholinesterase against (−)-cocaine: structural and energetic factors affecting the catalytic efficiency. Biochemistry. 2010;49:9113–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng F, Yang W, Ko M-C, Liu J, Cho H, Gao D, Tong M, Tai H-H, Woods JH, Zhan C-G. Most efficient cocaine hydrolase designed by virtual screening of transition states. J Am Chem Soc. 2008;130:12148–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng F, Zhan C-G. Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anti-cocaine medications. Future Med Chem. 2009;1:515–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng F, Zhan C-G. Rational design of an enzyme mutant for anti-cocaine therapeutics. J Comput Aided Mol Des. 2008a;22:661–71.

    Article  CAS  PubMed  Google Scholar 

  • Zheng F, Zhan C-G. Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose. Org Biomol Chem. 2008b;6:836–43.

    Article  CAS  PubMed  Google Scholar 

  • Zheng F, Zhan C-G. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse. PLoS Comput Biol. 2012;8(7):e1002610. doi:10.1371/journal.pcbi.1002610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmerman JL. Cocaine intoxication. Crit Care Clin. 2012;28:517–26.

    Article  PubMed  Google Scholar 

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Conflict of Interest Statement

Both authors hold patents related to some of the enzymes described in this paper.

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Authors and Affiliations

  1. Department of Pharmacology and Psychology, University of Michigan, Ann Arbor, MI, USA

    James H. Woods

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA

    Chang-Guo Zhan

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  1. James H. Woods
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  2. Chang-Guo Zhan
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Correspondence to James H. Woods .

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Editors and Affiliations

  1. National Institute on Drug Abuse, National Institutes of Health, Bethesda, USA

    Ivan D. Montoya

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Woods, J.H., Zhan, CG. (2016). Enzyme-Based Cocaine Pharmacotherapies: Current Status and Projections for the Future. In: Montoya, I. (eds) Biologics to Treat Substance Use Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-23150-1_10

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  • DOI: https://doi.org/10.1007/978-3-319-23150-1_10

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