Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment

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。目前还没有fda批准的抗可卡因药物。可卡因滥用造成的灾难性的医疗和社会后果使研制一种反可卡因药物成为高度优先事项。通过施用人丁基胆碱酯酶（BChE）来增强可卡因代谢被认为是治疗可卡因过量和成瘾的有效策略。然而，野生型BChE对天然存在的(-)-可卡因的催化效率（kcat/KM）较低（kcat = 4.1 min-1, KM = 4.5¿M）。然而，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），与野生型BChE相比，对(-)-可卡因的催化效率提高了1000倍。我们首次发现并获得专利的CocHs的体内证据和临床数据表明，我们发现的CocHs是开发抗可卡因药物的有希望的候选者。我们最近设计、发现并获得专利的CocHs效果更强。基于我们在合理设计和发现CocHs方面的成功，目前提出的研究重点是合理设计，制备和新型长效药物的临床前测试

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.