Grants and Contracts Details
Description
Cocaine abuse is a major medical and public health problem. There is still no FDA-approved anti-cocaine
medication. Disastrous medical and social consequences of cocaine abuse have made the development of an
anti-cocaine medication a high priority. Enhancing cocaine metabolism by administration of human
butyrylcholinesterase (BChE) is recognized as an efficient treatment strategy for cocaine overdose and
addiction. However, the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-
cocaine is low (kcat = 4.1 min-1 and KM = 4.5 ìM). Nevertheless, we have recently designed and discovered a
set of BChE mutants, known as cocaine hydrolases (CocHs), with >1,000-fold improved catalytic efficiency
against (-)-cocaine compared to wild-type BChE. In vivo evidences and clinical data for the first one of our
discovered and patented CocHs have demonstrated that our discovered CocHs are promising candidates for
development of an anti-cocaine medication. Our recently designed, discovered and patented CocHs are
significantly more potent. Built on our success in rational design and discovery of the CocHs, the currently
proposed investigation is focused on rational design, preparation, and preclinical testing of a novel type of
long-lasting CocH entities, denoted as Fc-CocH, obtained from fusion of CocH with Fc portion of human
antibody IgG1. The specific aims are: (1) to design new molecular entities of Fc-CocH that have not only a high
catalytic efficiency against (-)-cocaine, but also a long biological half-life; (2) to prepare reliable Fc-CocH
materials for in vivo studies in Aims 3 and 4 through scale-up protein production using stable cell lines followed
by in vitro kinetic analysis of the catalytic activity against (-)-cocaine; (3) to characterize the in vivo potency,
pharmacokinetics, and immunogenicity of Fc-CocHs in rats and rhesus monkeys; (4) to evaluate the actual
effects of the Fc-CocHs (identified in Aim 3) on the physiological and behavior responses of animals to cocaine
by performing cardiovascular assays and self-administration assays in rhesus monkeys. Accomplishment of
this proposed investigation will result in the identification and development of the best possible Fc-CocH entity
that has not only a high in vivo potency in blocking physiological effects of cocaine, but also a long biological
half-life without immunogenicity. The long-lasting Fc-CocH entity optimized in this investigation is expected to
be highly effective and safe as a novel exogenous enzyme suitable for cocaine addiction treatment in humans.
Status | Finished |
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Effective start/end date | 4/1/13 → 2/28/18 |
Funding
- National Institute on Drug Abuse: $3,363,303.00
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