RT Journal Article
SR Electronic
T1 Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 318
OP 323
DO 10.1124/mol.108.049486
VO 75
IS 2
A1 Gao, Daquan
A1 Narasimhan, Diwahar L.
A1 Macdonald, Joanne
A1 Brim, Remy
A1 Ko, Mei-Chuan
A1 Landry, Donald W.
A1 Woods, James H.
A1 Sunahara, Roger K.
A1 Zhan, Chang-Guo
YR 2009
UL http://molpharm.aspetjournals.org/content/75/2/318.abstract
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