ArticleMolecular pharmacology2011
Subunit stabilization and polyethylene glycolation of cocaine esterase improves in vivo residence time.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Strategic Approaches for Overcoming Peptide and Protein Drug Limitations.The protein journal · 2026Review
- A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future.Pharmaceutics · 2023Review
- Efficient Cocaine Degradation by Cocaine Esterase-Loaded Red Blood Cells.Frontiers in physiology · 2020Article
- The acid-base-nucleophile catalytic triad in ABH-fold enzymes is coordinated by a set of structural elements.PloS one · 2020Article
- Distinctive structural motifs co-ordinate the catalytic nucleophile and the residues of the oxyanion hole in the alpha/beta-hydrolase fold enzymes.Protein science : a publication of the Protein Society · 2019Article
- Polymer conjugation of proteins as a synthetic post-translational modification to impact their stability and activity.Polymer chemistry · 2019Article
- Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification.ACS chemical biology · 2014Article
- A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates.Translational psychiatry · 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
- 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
- Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.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
- 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
10 authors at 1 institution in 1 country.
Funding
Abstract
No small-molecule therapeutic is available to treat cocaine addiction, but enzyme-based therapy to accelerate cocaine hydrolysis in serum has gained momentum. Bacterial cocaine esterase (CocE) is the fastest known native enzyme that hydrolyzes cocaine. However, its lability at 37°C has limited its therapeutic potential. Cross-linking subunits through disulfide bridging is commonly used to stabilize multimeric enzymes. Herein we use structural methods to guide the introduction of two cysteine residues within dimer interface of CocE to facilitate intermolecular disulfide bond formation. The disulfide-crosslinked enzyme displays improved thermostability, particularly when combined with previously described mutations that enhance stability (T172R-G173Q). The newly modified enzyme yielded an extremely stable form of CocE (CCRQ-CocE) that retained greater than 90% of its activity after 41 days at 37°C, representing an improvement of more than 4700-fold over the wild-type enzyme. CCRQ-CocE could also be modified by polyethylene glycol (PEG) polymers, which improved its in vivo residence time from 24 to 72 h, as measured by a cocaine lethality assay, by self-administration in rodents, and by measurement of inhibition of cocaine-induced cardiovascular effects in rhesus monkeys. PEG-CCRQ elicited negligible immune response in rodents. Subunit stabilization and PEGylation has thus produced a potential protein therapeutic with markedly higher stability both in vitro and in vivo.
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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.