PT  - JOURNAL ARTICLE
AU  - Gao, Daquan
AU  - Narasimhan, Diwahar L.
AU  - Macdonald, Joanne
AU  - Brim, Remy
AU  - Ko, Mei-Chuan
AU  - Landry, Donald W.
AU  - Woods, James H.
AU  - Sunahara, Roger K.
AU  - Zhan, Chang-Guo
TI  - Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity
AID  - 10.1124/mol.108.049486
DP  - 2009 Feb 01
TA  - Molecular Pharmacology
PG  - 318--323
VI  - 75
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/75/2/318.short
4100  - http://molpharm.aspetjournals.org/content/75/2/318.full
SO  - Mol Pharmacol2009 Feb 01; 75
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics