TY - JOUR T1 - Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 318 LP - 323 DO - 10.1124/mol.108.049486 VL - 75 IS - 2 AU - Daquan Gao AU - Diwahar L. Narasimhan AU - Joanne Macdonald AU - Remy Brim AU - Mei-Chuan Ko AU - Donald W. Landry AU - James H. Woods AU - Roger K. Sunahara AU - Chang-Guo Zhan Y1 - 2009/02/01 UR - http://molpharm.aspetjournals.org/content/75/2/318.abstract N2 - 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 ER -