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 Zhan, Fang Zheng

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article number53
JournalAAPS Journal
Volume20
Issue number3
DOIs
StatePublished - May 1 2018

Bibliographical note

Publisher Copyright:
© 2018, American Association of Pharmaceutical Scientists.

Keywords

  • cocaine
  • drug abuse
  • metabolic enzyme
  • protein engineering

ASJC Scopus subject areas

  • Pharmaceutical Science

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