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Development of Fc-Fused Cocaine Hydrolase for Cocaine Addiction Treatment: Catalytic and Pharmacokinetic Properties

  • Research Article
  • Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017
  • Published:
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Abstract

Cocaine abuse is a worldwide public health and social problem without a US Food and Drug Administration (FDA)-approved medication. Accelerating cocaine metabolism that produces biologically inactive metabolites by administration of an efficient cocaine hydrolase (CocH) has been recognized as a promising strategy for cocaine abuse treatment. However, the therapeutic effects of CocH are limited by its short biological half-life (e.g., 8 h or shorter in rats). In this study, we designed and prepared a set of Fc-fusion proteins constructed by fusing Fc(M3) with CocH3 at the N-terminus of CocH3. A linker between the two protein domains was optimized to improve both the biological half-life and catalytic activity against cocaine. It has been concluded that Fc(M3)-G6S-CocH3 not only has fully retained the catalytic efficiency of CocH3 against cocaine but also has the longest biological half-life (e.g., ∼ 136 h in rats) among all of the long-acting CocHs identified so far. A single dose (0.2 mg/kg, IV) of Fc(M3)-G6S-CocH3 was able to significantly attenuate 15 mg/kg cocaine-induced hyperactivity for at least 11 days (268 h) after the Fc(M3)-G6S-CocH3 administration.

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References

  1. UNODC. World drug report 2014. New York: United Nations Publications; 2014.

    Google Scholar 

  2. Schrank KS. Cocaine-related emergency department presentations. NIDA Res Monogr. 1993;123:110–28.

    Google Scholar 

  3. Brim RL, Noon KR, Collins GT, Nichols J, Narasimhan D, Sunahara RK, et al. The ability of bacterial cocaine esterase to hydrolyze cocaine metabolites and their simultaneous quantification using high-performance liquid chromatography-tandem mass spectrometry. Mol Pharmacol. 2011;80(6):1119–27. https://doi.org/10.1124/mol.111.074534.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Abuse S, Administration MHS. The DAWN report: highlights of the 2011 drug abuse warning network (DAWN) findings on drug-related emergency department visits. Rockville: SAMHSA; 2012.

    Google Scholar 

  5. Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs. 2004;64:1547–73.

    Article  PubMed  CAS  Google Scholar 

  6. Huang X, Gu HH, Zhan C-G. Mechanism for cocaine blocking the transport of dopamine: insights from molecular modeling and dynamics simulations. J Phys Chem B. 2009;113(45):15057–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Yuan Y, Huang X, Midde NM, Quizon PM, Sun WL, Zhu J, et al. Molecular mechanism of HIV-1 tat interacting with human dopamine transporter. ACS Chem Neurosci. 2015;6:658–65.

    Article  PubMed  CAS  Google Scholar 

  8. Yuan Y, Huang X, Zhu J, Zhan C-G. Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcriptio. Future Med Chem. 2016;8:2077–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Skolnick P, White D, Acri JB. Editorial: emerging targets for stimulant use disorders: where to invest in an era of constrained resources? CNS Neurol Disord Drug Targets. 2015;14:691.

    Article  PubMed  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

  11. Zheng F, Zhan C-G. Enzyme therapy approaches for treatment of drug overdose and addiction. Future Med Chem. 2011;3:9–13.

    Article  PubMed  CAS  Google Scholar 

  12. Zheng F, Zhan C-G. Are pharmacokinetic approaches feasible for treatment of cocaine addiction and overdose? Future Med Chem. 2012;4:125–8.

    Article  PubMed  CAS  Google Scholar 

  13. Xue L, Hou S, Tong M, Fang L, Chen X, Jin Z, et al. Preparation and in vivo characterization of a cocaine hydrolase engineered from human butyrylcholinesterase for metabolizing cocaine. Biochem J. 2013;453(3):447–54. https://doi.org/10.1042/BJ20130549.

    Article  PubMed  CAS  Google Scholar 

  14. Howell L, Nye J, Stehouwer J, Voll R, Mun J, Narasimhan D, et al. A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates. Transl Psychiatry. 2014;4(7):e407. https://doi.org/10.1038/tp.2014.48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Collins GT, Narasimhan D, Cunningham AR, Zaks ME, Nichols J, Ko M-C, et al. Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats. Neuropsychopharmacology. 2012;37(5):1092–103. https://doi.org/10.1038/npp.2011.226.

    Article  PubMed  CAS  Google Scholar 

  16. Brimijoin S, Gao Y, Anker JJ, Gliddon LA, LaFleur D, Shah R, et al. A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats. Neuropsychopharmacology. 2008;33(11):2715–25. https://doi.org/10.1038/sj.npp.1301666.

    Article  PubMed  CAS  Google Scholar 

  17. Schindler CW, Justinova Z, Lafleur D, Woods D, Roschke V, Hallak H, et al. Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. Addict Biol. 2013;18(1):30–9. https://doi.org/10.1111/j.1369-1600.2011.00424.x.

    Article  PubMed  CAS  Google Scholar 

  18. Cohen-Barak O, Wildeman J, van de Wetering J, Hettinga J, Schuilenga-Hut P, Gross A, et al. Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated Butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects. J Clin Pharmacol. 2015;55:573–83. https://doi.org/10.1002/jcph.450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Shram MJ, Cohen-Barak O, Chakraborty B, Bassan M, Schoedel KA, Hallak H, et al. Assessment of pharmacokinetic and pharmacodynamic interactions between albumin-fused mutated butyrylcholinesterase and intravenously administered cocaine in recreational cocaine users. J Clin Psychopharmacol. 2015;35:396–405. https://doi.org/10.1097/JCP.0000000000000347.

    Article  PubMed  CAS  Google Scholar 

  20. 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:e1002610.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Sun H, Pang Y-P, Lockridge O, Brimijoin S. Re-engineering butyrylcholinesterase as a cocaine hydrolase. Mol Pharmacol. 2002;62(2):220–4.

    Article  PubMed  CAS  Google Scholar 

  22. Zheng F, Yang WC, Ko MC, Liu JJ, Cho H, Gao DQ, et al. Most efficient cocaine hydrolase designed by virtual screening of transition states. J Am Chem Soc. 2008;130(36):12148–55. https://doi.org/10.1021/ja803646t.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Xue L, Ko M-C, Tong M, Yang W, Hou S, Fang L, et al. Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine. Mol Pharmacol. 2011;79:290–7. https://doi.org/10.1124/mol.110.068494.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Fang L, Zheng F, Zhan C-G. A model of glycosylated human butyrylcholinesterase. Mol BioSyst. 2014;10:348–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Pan Y, Gao D, Yang W, Cho H, Yang G, Tai H-H, et al. Computational redesign of human butyrylcholinesterase for anticocaine medication. Proc Natl Acad Sci U S A. 2005;102(46):16656–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 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(1–3):148–52. https://doi.org/10.1016/j.cbi.2010.01.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Willyard C. Quest for the quitting pill. Nature. 2015;522:S53–5.

    Article  PubMed  CAS  Google Scholar 

  28. Chen X, Xue L, Hou S, Jin Z, Zhang T, Zheng F, et al. Long-acting cocaine hydrolase for addiction therapy. Proc Natl Acad Sci U S A. 2016;113:422–7.

    Article  PubMed  CAS  Google Scholar 

  29. Lo KM, Sudo Y, Chen J, Li Y, Lan Y, Kong S-M, et al. High level expression and secretion of Fc-X fusion proteins in mammalian cells. Protein Eng. 1998;11:495–500.

    Article  PubMed  CAS  Google Scholar 

  30. 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(1):83–7. https://doi.org/10.1016/j.cbi.2008.04.024.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ashani Y, Pistinner S. Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: a mathematically based toxicokinetic model. Toxicol Sci. 2004;77(2):358–67.

    Article  PubMed  CAS  Google Scholar 

  32. Huang Y-J, Huang Y, Baldassarre H, Wang B, Lazaris A, Leduc M, et al. Recombinant human butyrylcholinesterase from milk of transgenic animals to protect against organophosphate poisoning. Proc Natl Acad Sci U S A. 2007;104(34):13603–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Lockridge O, Blong RM, Masson P, Froment M-T, Millard CB, Broomfield CA. A single amino acid substitution, Gly117His, confers phosphotriesterase (organophosphorus acid anhydride hydrolase) activity on human butyrylcholinesterase. Biochemistry. 1997;36(4):786–95.

    Article  PubMed  CAS  Google Scholar 

  34. Schneider JD, Marillonnet S, Castilho A, Gruber C, Werner S, Mach L, et al. Oligomerization status influences subcellular deposition and glycosylation of recombinant butyrylcholinesterase in Nicotiana benthamiana. Plant Biotechnol J. 2014;12(7):832–9. https://doi.org/10.1111/pbi.12184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lockridge O. Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol Ther. 2015;148:34–46. https://doi.org/10.1016/j.pharmthera.2014.11.011.

    Article  PubMed  CAS  Google Scholar 

  36. Chilukuri N, Parikh K, Sun W, Naik R, Tipparaju P, Doctor B, et al. Polyethylene glycosylation prolongs the circulatory stability of recombinant human butyrylcholinesterase. Chem Biol Interact. 2005;157:115–21.

    Article  PubMed  CAS  Google Scholar 

  37. Huang Y-J, Lundy PM, Lazaris A, Huang Y, Baldassarre H, Wang B, et al. Substantially improved pharmacokinetics of recombinant human butyrylcholinesterase by fusion to human serum albumin. BMC Biotechnol. 2008;8(1):50. https://doi.org/10.1186/1472-6750-8-50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gilgun-Sherki Y, Eliaz RE, McCann DJ, Loupe PS, Eyal E, Blatt K, et al. Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence. Drug Alcohol Depend. 2016;166:13–20.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institutes of Health (NIH grants UH2/UH3 DA041115, R01 DA035552, R01 DA032910, R01 DA013930, and R01 DA025100) and the National Science Foundation (NSF grant CHE-1111761).

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Authors and Affiliations

  1. Molecular Modeling and Biopharmaceutical Center (MMBC) and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA

    Xiabin Chen, Jing Deng, Wenpeng Cui, Shurong Hou, Jinling Zhang, Xirong Zheng, Xin Ding, Huimei Wei, Ziyuan Zhou, Kyungbo Kim, Chang-Guo Zhan & Fang Zheng

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  1. Xiabin Chen
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  2. Jing Deng
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  3. Wenpeng Cui
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  11. Chang-Guo Zhan
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  12. Fang Zheng
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Corresponding authors

Correspondence to Chang-Guo Zhan or Fang Zheng.

Ethics declarations

Experiments were performed in a same colony room in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health. The animal protocol was approved by the IACUC (Institutional Animal Care and Use Committee) at the University of Kentucky.

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The authors declare that they have no conflict of interest.

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Guest Editors: Shraddha Thakkar and Cesar M. Compadre

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Chen, X., Deng, J., Cui, W. et al. Development of Fc-Fused Cocaine Hydrolase for Cocaine Addiction Treatment: Catalytic and Pharmacokinetic Properties. AAPS J 20, 53 (2018). https://doi.org/10.1208/s12248-018-0214-9

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  • DOI: https://doi.org/10.1208/s12248-018-0214-9

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