Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity

D Gao; D L Narasimhan; Joanne Macdonald; R Brim; M-C Ko; D W Landry; J H Woods; R K Sunahara; C-G Zhan

doi:10.1124/mol.108.049486

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Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity

Journal article

Peer reviewed

Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity

D Gao, D L Narasimhan, Joanne Macdonald, R Brim, M-C Ko, D W Landry, J H Woods, R K Sunahara and C-G Zhan

Molecular Pharmacology, Vol.75(2), pp.318-323

2009

DOI: https://doi.org/10.1124/mol.108.049486

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Abstract

cocaine

toxicity

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.

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Title: Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity
Authors: D Gao (Author) - University of Kentucky, United States
D L Narasimhan (Author) - University of Michigan, United States
Joanne Macdonald (Author) - Colombia University, United States
R Brim (Author) - University of Michigan, United States
M-C Ko (Author) - University of Michigan, United States
D W Landry (Author) - Colombia University, United States
J H Woods (Author) - University of Michigan, United States
R K Sunahara (Author) - University of Michigan, United States
C-G Zhan (Author) - University of Kentucky, United States
Publication details: Molecular Pharmacology, Vol.75(2), pp.318-323
Publisher: American Society for Pharmacology and Experimental Therapeutics
Date published: 2009
DOI: 10.1124/mol.108.049486
ISSN: 0026-895X
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450221802621
Output Type: Journal article

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Web Of Science research areas: Pharmacology & Pharmacy

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