Application of artificial enzymes to the problem of cocaine.
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.
Division of Clinical Pharmacology and Experimental Therapeutics, Columbia University, New York, New York 10032, USA.
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De Prada
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Winger
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Landry
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002384:Catalysis; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000628:therapy*; D006801:Humans; D006868:Hydrolysis; D051379:Mice
D000911:Antibodies, Monoclonal; D003042:Cocaine