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The AAPS Journal

, 20:53 | Cite as

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

  • Xiabin Chen
  • Jing Deng
  • Wenpeng Cui
  • Shurong Hou
  • Jinling Zhang
  • Xirong Zheng
  • Xin Ding
  • Huimei Wei
  • Ziyuan Zhou
  • Kyungbo Kim
  • Chang-Guo ZhanEmail author
  • Fang ZhengEmail author
Research Article Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017
Part of the following topical collections:
  1. Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017

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.

KEY WORDS

cocaine drug abuse metabolic enzyme protein engineering 

Notes

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).

Compliance with Ethical Standards

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.

Competing Interest

The authors declare that they have no conflict of interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Xiabin Chen
    • 1
  • Jing Deng
    • 1
  • Wenpeng Cui
    • 1
  • Shurong Hou
    • 1
  • Jinling Zhang
    • 1
  • Xirong Zheng
    • 1
  • Xin Ding
    • 1
  • Huimei Wei
    • 1
  • Ziyuan Zhou
    • 1
  • Kyungbo Kim
    • 1
  • Chang-Guo Zhan
    • 1
    Email author
  • Fang Zheng
    • 1
    Email author
  1. 1.Molecular Modeling and Biopharmaceutical Center (MMBC) and Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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