Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

Fang Zheng, Zhenyu Jin, Jing Deng, Xiabin Chen, Xirong Zheng, Guojun Wang, Kyungbo Kim, Linyue Shang, Ziyuan Zhou, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism via hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment. However, the biological half-life of TV-1380 (t1/2= 8 h in rats, associated with t1/2= 43-77 h in humans) is not long enough for practical treatment of cocaine dependence, which requires enzyme injection for no more than once weekly. Through protein fusion of a human butyrylcholinesterase mutant (denoted as CocH5) with a mutant (denoted as Fc(M6)) of Fc from human IgG1, we have designed, prepared, and tested a new fusion protein (denoted as CocH5-Fc(M6)) for its pharmacokinetic profile and in vivo catalytic activity against (-)-cocaine. CocH5-Fc(M6) represents the currently most efficient long-acting cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest elimination half-life (t1/2= 229 ± 5 h) in rats. As a result, even at a single modest dose of 3 mg/kg, CocH5-Fc(M6) can significantly and effectively accelerate the metabolism of cocaine in rats for at least 60 days. In addition, ∼70 nM CocH5-Fc(M6) in plasma was able to completely block the toxicity and physiological effects induced by intraperitoneal injection of a lethal dose of cocaine (60 mg/kg).

Original languageEnglish
Pages (from-to)1340-1349
Number of pages10
JournalBioconjugate Chemistry
Volume33
Issue number7
DOIs
StatePublished - Jul 20 2022

Bibliographical note

Funding Information:
This work was funded in part by the National Institutes of Health (NIH Grants U01 DA051079, UH2/UH3 DA041115, U18 DA052319, R01 DA056646, R01 DA035552, R01 DA032910, and R01 DA013930) and the National Science Foundation (NSF Grant CHE-1111761).

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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