Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase Mutant with Improved Binding Affinity to Neonatal Fc Receptor for Treatment of Cocaine Abuse

Fang Zheng, Xiabin Chen, Kyungbo Kim, Ting Zhang, Haifeng Huang, Shuo Zhou, Jinling Zhang, Zhenyu Jin, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fusion CocH binding with neonatal Fc receptor (FcRn) in the present study. This approach led to the design and testing of CocH3-Fc(M6), a CocH3-Fc mutant with nearly 100-fold increased binding affinity: from Kd = ~ 4 μM to Kd = 43 nM. As a result, CocH3-Fc(M6) indeed revealed a markedly prolonged biological half-life (t1/2 = 206 ± 7 h or ~ 9 days) in rats, longer than other known Fc-fusion protein drugs such as abatacept and alefacept (for other therapeutic purposes) in the same species (rats). It has been demonstrated that a single dose of 3 mg/kg CocH3-Fc(M6) effectively blocked 20 mg/kg cocaine-induced hyperactivity on day 18 after CocH3-Fc(M6) administration. This is the first attempt to rationally design long-acting Fc-fusion enzyme mutant based on combined computational modeling and experimental measurement of the Fc-fusion CocH binding with FcRn. The similar structure-based design strategy may be used to prolong the biological half-lives of other Fc-fusion protein drugs.

Original languageEnglish
Article number62
JournalAAPS Journal
Volume22
Issue number3
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2020, American Association of Pharmaceutical Scientists.

Keywords

  • biological half-life
  • cocaine abuse
  • cocaine hydrolase
  • enzyme therapy
  • protein drug

ASJC Scopus subject areas

  • Pharmaceutical Science

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