ArticleProtein engineering, design & selection : PEDS2010
Structural analysis of thermostabilizing mutations of cocaine esterase.
Article in Protein engineering, design & selection : PEDS, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- TargetingPharmaceuticals (Basel, Switzerland) · 2025Article
- Homologous Pairs of Low and High Temperature Originating Proteins Spanning the Known Prokaryotic Universe.Scientific data · 2023Article
- Characterization of a thermostable Cas13 enzyme for one-pot detection of SARS-CoV-2.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Empirical comparison and analysis of machine learning-based predictors for predicting and analyzing of thermophilic proteins.EXCLI journal · 2022Review
- The acid-base-nucleophile catalytic triad in ABH-fold enzymes is coordinated by a set of structural elements.PloS one · 2020Article
- Bacterial DNA induces the formation of heat-resistant disease-associated proteins in human plasma.Scientific reports · 2019Observational
- A thermostable Cas9 with increased lifetime in human plasma.Nature communications · 2017Article
- Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations.Chemico-biological interactions · 2016Article
- Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification.ACS chemical biology · 2014Article
- A highly efficient cocaine-detoxifying enzyme obtained by computational design.Nature communications · 2014Article
- Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys.The Journal of pharmacology and experimental therapeutics · 2012Article
- Cell permeable cocaine esterases constructed by chemical conjugation and genetic recombination.Molecular pharmaceutics · 2012Article
- Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2012Article
- Cocaine esterase-cocaine binding process and the free energy profiles by molecular dynamics and potential of mean force simulations.The journal of physical chemistry. B · 2012Article
- Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.Future medicinal chemistry · 2012Review
- Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity.Future medicinal chemistry · 2012Review
- The fate of bacterial cocaine esterase (CocE): an in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination.The Journal of pharmacology and experimental therapeutics · 2012Article
- Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs.Drug and alcohol dependence · 2011Article
- Subunit stabilization and polyethylene glycolation of cocaine esterase improves in vivo residence time.Molecular pharmacology · 2011Article
- The ability of bacterial cocaine esterase to hydrolyze cocaine metabolites and their simultaneous quantification using high-performance liquid chromatography-tandem mass spectrometry.Molecular pharmacology · 2011Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Cocaine is considered to be the most addictive of all substances of abuse and mediates its effects by inhibiting monoamine transporters, primarily the dopamine transporters. There are currently no small molecules that can be used to combat its toxic and addictive properties, in part because of the difficulty of developing compounds that inhibit cocaine binding without having intrinsic effects on dopamine transport. Most of the effective cocaine inhibitors also display addictive properties. We have recently reported the use of cocaine esterase (CocE) to accelerate the removal of systemic cocaine and to prevent cocaine-induced lethality. However, wild-type CocE is relatively unstable at physiological temperatures (tau(1/2) approximately 13 min at 37 degrees C), presenting challenges for its development as a viable therapeutic agent. We applied computational approaches to predict mutations to stabilize CocE and showed that several of these have increased stability both in vitro and in vivo, with the most efficacious mutant (T172R/G173Q) extending half-life up to 370 min. Here we present novel X-ray crystallographic data on these mutants that provide a plausible model for the observed enhanced stability. We also more extensively characterize the previously reported variants and report on a new stabilizing mutant, L169K. The improved stability of these engineered CocE enzymes will have a profound influence on the use of this protein to combat cocaine-induced toxicity and addiction in humans.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.