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Description
Cocaine abuse is a major public health problem that directly or indirectly affects almost every community
and family in some way. There is still no FDA-approved medication specific for cocaine addiction or overdose.
Disastrous medical and social consequences of cocaine abuse have made a high priority the development of
an anti-cocaine medication. Accelerating cocaine metabolism that produces biologically inactive metabolites
via a route similar to the principal cocaine-metabolizing pathway, i.e. cocaine hydrolysis catalyzed by human
butyrylcholinesterase (BChE) in plasma, is recognized as the most 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 at least 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 enzyme therapy for cocaine abuse. Our recently designed, discovered, and
patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine, but also
much longer biological half-lives. Built on our success in rational design and discovery of the highly efficient
CocHs and their long-acting forms (LAFs or CocH-LAFs), this investigation will focus on further optimization,
manufacturing process development, formulation development, and preclinical testing of the most promising
CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to
optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine, but also a
long biological half-life; (2) to test feasibility of large-scale CocH-LAF expression of promising CocH-LAF
entities; (3) to develop manufacturing processes for the most promising CocH-LAF (selected in Aim 2) in largescale;
(4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in
animal models of cocaine addiction by using the CocH-LAF material produced in Aim 3. The most promising
CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel
exogenous enzyme suitable for a monthly dosing schedule in the cocaine addiction treatment in humans. This
investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing
Practices) protein manufacturing, Investigational New Drug (IND)-enabling studies, and subsequent clinical
trials. Thus, this investigation will move the cocaine addiction treatment development closer to FDA approval.
Status | Finished |
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Effective start/end date | 9/15/15 → 7/31/22 |
Funding
- National Institute on Drug Abuse: $886,834.00
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Projects
- 1 Finished
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Scope: Carry-forward: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
Zhan, C.-G. (PI), Walsh, S. (CoI) & Zheng, F. (CoI)
National Institute on Drug Abuse
9/15/15 → 7/31/21
Project: Research project