Application of artificial enzymes to the problem of cocaine

Paloma De Prada, Gail Winger, Donald W. Landry

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cocaine mediates its reinforcing and toxic actions through a 'loss of function' effect at multiple receptors. The difficulties inherent in blocking a pleiotropic blocker pose a great obstacle for the classical receptor-antagonist approach and have contributed to the failure-to-date to devise specific treatments for cocaine overdose and addiction. As an alternative, we have embarked on an investigation of catalytic antibodies, a programmable class of artificial enzyme, as 'peripheral blockers' - agents designed to bind and degrade cocaine in the circulation before it partitions into the central nervous system to exert reinforcing or toxic effects. We synthesized transition-state analogs of cocaine's hydrolysis at its benzoyl ester, immunized mice, prepared hybridomas, and developed the first anti-cocaine catalytic antibodies with the capacity to degrade cocaine to non-reinforcing, non-toxic products. We subsequently identified several families of anti-cocaine catalytic antibodies and found that out most potent antibody, Mab15A10, possessed sufficient activity to block cocaine-induced reinforcement and sudden death in rodent models of addiction and overdose, respectively. With the potential to promote cessation of use, prolong abstinence, and provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume909
DOIs
StatePublished - 2000
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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