Development of Esterases for the Treatment of Cocaine Overdose and Abuse

开发用于治疗可卡因过量和滥用的酯酶

• 批准号: 7228552
• 负责人: james H Woods
• 金额: $ 67.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-10 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228552
• 关键词: Bacteria; Behavioral; Butyrylcholinesterase; Carbon; Coca; Cocaine; Cocaine Abuse; Development; Drug Kinetics; Endotoxins; Enzymes; Erythrocytes; Evaluation; Genetic Engineering; Heating; Human; Human Engineering; In Vitro; Metabolism; Modeling; Mus; Nitrogen; Outcome; Overdose; Plants; Procedures; Proteins; Rate; Rattus; Rhodococcus; Rodent Model; Source; South America; Techniques; Testing; Toxic effect; base; cocaine esterase; design; esterase; immunogenicity; improved; in vivo; insight; prevent; protective effect

DESCRIPTION (provided by applicant): Cocaine esterase (CocE) is a product of the bacterium Rhodococcus sp. which grows in the rhizosphere of coca plants in South America. The bacterium uses cocaine as its sole source of carbon and nitrogen, synthesizing CocE to initiate metabolism of the cocaine CocE is the most efficient enzyme (7.2 X 108) for metabolizing cocaine yet identified. It can both prevent and reverse extreme cocaine toxicity in our rodent models, and it has the potential to be developed into the first useful antagonist of cocaine's toxic effects. This proposal contains studies to continue to evaluate this enzyme in mouse and rat models of cocaine toxicity, to compare its effects with other protein-based anti-cocaine enzymes, and to use a variety of in vitro techniques, including pegylation and insertion into red blood cells, to improve this or other enzymes by reducing their antigenicity, and heat liability. These procedures are designed to prolong the enzyme's duration of action with the hopeful outcome that some insight will be obtained into how to make this substance useful in the long-term treatment of cocaine abuse.

描述（由申请人提供）：可卡因酯酶（CocE）是红球菌属细菌的产物。生长在南美洲古柯植物的根际。该细菌使用可卡因作为其唯一的碳和氮来源，合成 CocE 来启动可卡因代谢 CocE 是迄今为止已确定的代谢可卡因最有效的酶 (7.2 X 108)。它可以预防和逆转我们的啮齿动物模型中的极端可卡因毒性，并且有可能被开发成第一个有用的可卡因毒性作用拮抗剂。该提案包含继续在小鼠和大鼠可卡因毒性模型中评估这种酶的研究，将其与其他基于蛋白质的抗可卡因酶的效果进行比较，并使用各种体外技术，包括聚乙二醇化和插入红血中细胞，通过降低其抗原性和热敏感性来改善这种酶或其他酶。这些程序旨在延长酶的作用持续时间，希望能够获得一些关于如何使这种物质用于长期治疗可卡因滥用的见解。