Bacterial cocaine esterase: A protein-based therapy for cocaine overdose and addiction

Diwahar Narasimhan, James H. Woods, Roger K. Sunahara

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations

Abstract

Cocaine is highly addictive and there are no pharmacotherapeutic drugs available to treat acute cocaine toxicity or chronic abuse. Antagonizing an inhibitor such as cocaine using a small molecule has proven difficult. The alternative approach is to modify cocaine's pharmacokinetic properties by sequestering or hydrolyzing it in serum and limiting access to its sites of action. We took advantage of a bacterial esterase (CocE) that has evolved to hydrolyze cocaine and have developed it as a therapeutic that rapidly and specifically clears cocaine from the subject. Native enzyme was unstable at 37°C, thus limiting CocE's potential. Innovative computational methods based on the protein's structure helped elucidate its mechanism of destabilization. Novel protein engineering methodologies were applied to substantially improve its stability in vitro and in vivo. These improvements rendered CocE as a powerful and efficacious therapeutic to treat cocaine intoxication and lead the way towards developing a therapy for addiction.

Original languageEnglish (US)
Pages (from-to)137-150
Number of pages14
JournalFuture Medicinal Chemistry
Volume4
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • Process of covalently attaching polyethylene glycol polymer to a drug molecule (small molecule
  • protein
  • virus or peptide) to alter the pharmacokinetic and pharmacodynamic properties of the drug molecule

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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