Cocaine esterase (CocE) is a product of the bacterium Rhodococcus sp. which grows in the rhizosphere of coca plants in South America. The bacterium uses cocaine as its sole source of carbon and nitrogen, synthesizing CocE to initiate metabolism of the cocaine CocE is the most efficient enzyme (7.2 X 108) for metabolizing cocaine yet identified. It can both prevent and reverse extreme cocaine toxicity in our rodent models, and it has the potential to be developed into the first useful antagonist of cocaine's toxic effects. This proposal contains studies to continue to evaluate this enzyme in mouse and rat models of cocaine toxicity, to compare its effects with other protein-based anti-cocaine enzymes, and to use a variety of in vitro techniques, including pegylation and insertion into red blood cells, to improve this or other enzymes by reducing their antigenicity, and heat liability. These procedures are designed to prolong the enzyme's duration of action with the hopeful outcome that some insight will be obtained into how to make this substance useful in the long-term treatment of cocaine abuse. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021416-03
Application #
7407488
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
2006-05-10
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
3
Fiscal Year
2008
Total Cost
$684,627
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Collins, Gregory T; Narasimhan, Diwahar; Cunningham, Alyssa R et al. (2012) Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats. Neuropsychopharmacology 37:1092-103
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Brim, Remy L; Noon, Kathleen R; Collins, Gregory T et al. (2012) The fate of bacterial cocaine esterase (CocE): an in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination. J Pharmacol Exp Ther 340:83-95
Zheng, Fang; Zhan, Chang-Guo (2012) Are pharmacokinetic approaches feasible for treatment of cocaine addiction and overdose? Future Med Chem 4:125-8
Collins, Gregory T; Zaks, Matthew E; Cunningham, Alyssa R et al. (2011) Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats. Drug Alcohol Depend 118:158-65
Zheng, Fang; Zhan, Chang-Guo (2011) Enzyme-therapy approaches for the treatment of drug overdose and addiction. Future Med Chem 3:9-13
Liu, Junjun; Zhao, Xinyun; Yang, Wenchao et al. (2011) Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: unexpected common rate-determining step. J Phys Chem B 115:5017-25

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