Kinetic characterization of an efficient cocaine hydrolase against toxic metabolites of cocaine

Zhan, Max; Hou, Shurong; Shang, Linyue; Chen, Xiabin; Zhan, Chang‐Guo; Zheng, Fang

doi:10.1039/d3ob00374d

Cited by 1 publication

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“…To improve the catalytic efficiency of human BChE against (−)-cocaine, we developed a structure and mechanism-based computational enzyme redesign approach 28 – 31 . The structure and mechanism-based computational enzyme redesign followed by experimental studies led to successful design and discovery of a series of new BChE mutants with considerably improved catalytic efficiency against (−)-cocaine and its toxic metabolites compared to the wild-type 32 – 36 . Particularly, our computationally designed BChE mutants with ≥ 1000-fold improved catalytic efficiency against cocaine compared to wild-type BChE 37 – 40 are recognized as the true cocaine hydrolases (CocHs) in literature 41 – 45 .…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

Shang,

Wei,

Deng

et al. 2024

Sci Rep

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It is recognized as a promising therapeutic strategy for cocaine use disorder to develop an efficient enzyme which can rapidly convert cocaine to physiologically inactive metabolites. We have designed and discovered a series of highly efficient cocaine hydrolases, including CocH5-Fc(M6) which is the currently known as the most efficient cocaine hydrolase with both the highest catalytic activity against (−)-cocaine and the longest biological half-life in rats. In the present study, we characterized the time courses of protein appearance, pH, structural integrity, and catalytic activity against cocaine in vitro and in vivo of a CocH5-Fc(M6) bulk drug substance produced in a bioreactor for its in vitro and in vivo stability after long-time storage under various temperatures (− 80, − 20, 4, 25, or 37 °C). Specifically, all the tested properties of the CocH5-Fc(M6) protein did not significantly change after the protein was stored at any of four temperatures including − 80, − 20, 4, and 25 °C for ~ 18 months. In comparison, at 37 °C, the protein was less stable, with a half-life of ~ 82 days for cocaine hydrolysis activity. Additionally, the in vivo studies further confirmed the linear elimination PK profile of CocH5-Fc(M6) with an elimination half-life of ~ 9 days. All the in vitro and in vivo data on the efficacy and stability of CocH5-Fc(M6) have consistently demonstrated that CocH5-Fc(M6) has the desired in vitro and in vivo stability as a promising therapeutic candidate for treatment of cocaine use disorder.

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Section: Introductionmentioning

confidence: 99%

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

Shang,

Wei,

Deng

et al. 2024

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

Kinetic characterization of an efficient cocaine hydrolase against toxic metabolites of cocaine

Abstract: In the presence of alcohol, cocaine metabolism produces a number of metabolites, including three toxic ones (cocaethylene, norcocaine, and norcocaethylene) that are all more toxic than cocaine itself, with the...

Cited by 1 publication

References 56 publications

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

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