期刊
MOLECULAR PHARMACOLOGY
卷 75, 期 2, 页码 318-323出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.108.049486
关键词
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资金
- NIDA NIH HHS [DA021416, R01 DA013930, R01 DA013930-05, DA025100, R01 DA025100, DA013930, R01 DA013930-06, R01 DA025100-01] Funding Source: Medline
- NIGMS NIH HHS [GM007767] Funding Source: Medline
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 degrees 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 similar to 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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