title: Long-acting cocaine hydrolase for addiction therapy.
abstract: Cocaine abuse is a world-wide public health and social problem without a US Food and Drug Administration-approved medication. An ideal anticocaine medication would accelerate cocaine metabolism, producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Our recent studies have led to the discovery of the desirable, highly efficient cocaine hydrolases (CocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of the CNS. Preclinical and clinical data have demonstrated that these CocHs are safe for use in humans and are effective for accelerating cocaine metabolism. However, the actual therapeutic use of a CocH in cocaine addiction treatment is limited by its short biological half-life (e.g., 8 h or shorter in rats). Here we demonstrate a novel CocH form, a catalytic antibody analog, which is a fragment crystallizable (Fc)-fused CocH dimer (CocH-Fc) constructed by using CocH to replace the Fab region of human IgG1. The CocH-Fc not only has a high catalytic efficiency against cocaine but also, like an antibody, has a considerably longer biological half-life (e.g., ∼107 h in rats). A single dose of CocH-Fc was able to accelerate cocaine metabolism in rats even after 20 d and thus block cocaine-induced hyperactivity and toxicity for a long period. Given the general observation that the biological half-life of a protein drug is significantly longer in humans than in rodents, the CocH-Fc reported in this study could allow dosing once every 2-4 wk, or longer, for treatment of cocaine addiction in humans.
authors.affiliation: Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536.
authors.forename: Xiabin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536.
authors.forename: Liu
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536.
authors.forename: Shurong
authors.initials: S
authors.lastname: Hou
authors.affiliation: Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 zhan@uky.edu fzhen2@email.uky.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 zhan@uky.edu fzhen2@email.uky.edu.
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D000818:Animals; D055162:Biocatalysis; D002265:Carboxylic Ester Hydrolases / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D003042:Cocaine / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008958:Models, Molecular; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000378:metabolism; D013997:Time Factors
chemical_list: D011961:Receptors, Fc; D002265:Carboxylic Ester Hydrolases; D003042:Cocaine
keywords: cocaine addiction; drug abuse; enzyme therapy; protein engineering