Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment

用于可卡因成瘾治疗的长效可卡因代谢酶

• 批准号: 8636423
• 负责人: CHANG-GUO ZHAN
• 金额: $ 109.77万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636423
• 关键词: Animals; Antibodies; Behavior; Binding; Binding Sites; Biological; Biological Assay; Butyrylcholinesterase; Cardiovascular system; Clinical; Clinical Data; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Computer Simulation; Data; Development; Dose; Drug Kinetics; Enzymes; FDA approved; Goals; Half-Life; Human; Hydrolase; IgG1; Immunoglobulin G; In Vitro; Investigation; Investigational Drugs; Lead; Legal patent; Macaca mulatta; Medical; Metabolism; Molecular; Neuraxis; Neurons; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Plasma; Preclinical Testing; Preparation; Proteins; Public Health; Rattus; Schedule; Self Administration; Testing; Vaccines; addiction; base; cocaine overdose; design; immunogenicity; improved; in vitro Assay; in vitro activity; in vivo; large scale production; mutant; novel; novel therapeutics; public health relevance; response; small molecule; social; stable cell line; success; therapy development; treatment strategy

DESCRIPTION (provided by applicant): 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 ¿M). 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 potentially have not only a high catalytic efficiency against (-)-cocaine, but also a long biologicl half-life; (2) to prepare and test the designed Fc-CocHs for their in vitro activities; (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 promising 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.

描述（由申请人提供）： 可卡因滥用是一个重大的医疗和公共卫生问题 目前尚无 FDA 批准的抗可卡因药物。可卡因滥用造成的灾难性医疗和社会后果使得抗可卡因药物的开发成为一个高度关注的问题。通过施用人丁酰胆碱酯酶（BChE）增强可卡因代谢被认为是可卡因过量和成瘾的有效治疗策略，但是其催化效率（kcat / KM）。野生型 BChE 对天然存在的 (-)- 可卡因的活性较低（kcat = 4.1 min-1 且 KM = 4.5 ¿M），尽管如此，我们最近设计并发现了一组 BChE 突变体，称为可卡因水解酶 (CocHs)。 ），与我们发现的第一个野生型 BChE 相比，其针对 (-)-可卡因的催化效率提高了 1,000 倍以上。和专利的 CocH 已经证明，我们发现的 CocH 是开发抗可卡因药物的有希望的候选者。基于我们在合理设计和发现 CocH 方面的成功，目前提出的 CocH 显着更有效。研究重点是一种新型长效药物的合理设计、制备和临床前测试 CocH实体，表示为Fc-CocH，由CocH与人抗体IgG1的Fc部分融合获得。具体目标是：（1）设计新的Fc-CocH分子实体，其不仅具有针对（的）高催化效率。 -)-可卡因，而且具有较长的生物半衰期；(2) 制备并测试设计的 Fc-CocH 的体外活性；(3) 表征其体内活性； Fc-CocHs 在大鼠和恒河猴中的效力、药代动力学和免疫原性；(4) 通过进行心血管测定来评估有前途的 Fc-CocHs（目标 3 中确定的）对动物对可卡因的生理和行为反应的实际影响；完成这项拟议的研究将导致鉴定和开发出最好的 Fc-CocH 实体，该实体不仅具有高的 Fc-CocH 实体。本次研究中优化的长效Fc-CocH实体有望作为一种适用于可卡因成瘾治疗的新型外源性酶，具有高效、安全的体内阻断可卡因生理效应的作用，而且具有较长的生物半衰期。在人类中。