Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity

Daquan Gao, Diwahar L. Narasimhan, Joanne Macdonald, Remy Brim, Mei Chuan Ko, Donald W. Landry, James H. Woods, Roger K. Sunahara, Chang Guo Zhan

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction, because CocE is the most efficient native enzyme for metabolizing the naturally occurring cocaine yet identified. A major obstacle to the clinical application of CocE is the thermoinstability of native CocE with a half-life of only a few minutes at physiological temperature (37°C). Here we report thermostable variants of CocE developed through rational design using a novel computational approach followed by in vitro and in vivo studies. This integrated computational-experimental effort has yielded a CocE variant with a ∼30-fold increase in plasma half-life both in vitro and in vivo. The novel design strategy can be used to develop thermostable mutants of any protein.

Original languageEnglish (US)
Pages (from-to)318-323
Number of pages6
JournalMolecular pharmacology
Volume75
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Gao, D., Narasimhan, D. L., Macdonald, J., Brim, R., Ko, M. C., Landry, D. W., Woods, J. H., Sunahara, R. K., & Zhan, C. G. (2009). Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Molecular pharmacology, 75(2), 318-323. https://doi.org/10.1124/mol.108.049486