Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.
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.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Diwahar
D
Narasimhan
James H
JH
Woods
Roger K
RK
Sunahara
D000818:Animals; D001419:Bacteria / Q000201:enzymology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D003042:Cocaine / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000201:enzymology* / Q000628:therapy; D062787:Drug Overdose; D004795:Enzyme Stability; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D014612:Vaccines / Q000627:therapeutic use
D014612:Vaccines; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D002091:Butyrylcholinesterase; D003042:Cocaine