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Application of Artificial Enzymes to the Problem of Cocaine
Author(s) -
DE PRADA PALOMA,
WINGER GAIL,
LANDRY DONALD W.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06681.x
Subject(s) - addiction , pharmacology , receptor , drug , enzyme , antibody , chemistry , medicine , biochemistry , immunology , psychiatry
A bstract : 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.