SECRETASE INHIBITORS FOR TREATING ALZHEIMER'S DISEASE

描述：申请人的实验室最近克隆了β-分泌酶， 命名为Memapsin 2(M2)。这是一种关键的人脑天冬氨酸蛋白酶，参与 从淀粉样前体蛋白(APP)和 阿尔茨海默病(AD)的发展。在这项建议中，邓博士计划 开发治疗阿尔茨海默病的M2抑制剂。申请人 在天冬氨酸蛋白酶的开发方面有丰富的经验和成功的经验 治疗HIV感染的抑制剂药物及其渗透性 穿过血脑屏障。开发的两种M2抑制剂原型 申请人的实验室显示出很强的抑制作用。这项建议是 重点关注两个主要目标：1)获取有关M2的必要信息 开发抑制剂设计，以及2)设计和测试M2抑制剂 治疗潜力。为了达到第一个目标，M2衬底 特异性将被确定，含有M2的囊泡将从 细胞，X-射线晶体结构的M2和M2-抑制剂络合物 并将获得的人和小鼠的M2进行比较，以验证测试的有效性 在PDAPP转基因小鼠中M2抑制剂的作用。对于第二个目的，随机剩余 将筛选过渡态抑制物库以确定M2残留量 对抑制的偏好，以及设计小尺寸、有效的抑制剂。这些 抑制剂将在酶、细胞和动物模型中进行测试。M2 研究和抑制剂测试将在申请人的实验室进行。这个 联合调查员戈什博士将进行抑制剂的合成。

DESCRIPTION: The applicant's laboratory has recently cloned beta-secretase, named memapsin 2 (M2). This is a key human brain aspartic protease involved in the production of Abeta from the amyloid precursor protein (APP) and the development of Alzheimer's disease (AD). In this proposal, Dr Tang plans to develop M2 inhibitors for the treatment of Alzheimer's disease. The applicant has extensive experience and success in the development of aspartic protease inhibitor drugs for the treatment of HIV infection, and their penetration through the blood brain barrier. Two prototype M2 inhibitors developed in the applicant's laboratory show a potent inhibitory effect. This proposal is focused on two main objectives; 1) to acquire the necessary information on M2 to develop inhibitor design, and 2) to design and test M2 inhibitors with a therapeutic potential. For attaining the first objective, M2 substrate specificity will be determined, M2 containing vesicles will be isolated from cells, x-ray crystal structure of M2 and M2-inhibitor complexes will be obtained, and the human and mouse M2 will be compared to validate the testing of M2 inhibitors in PDAPP transgenic mice. For the second Aim, a random-residue transition-state inhibitor library will be screened to determine M2 residue preferences for inhibition and to design small sized, potent inhibitors. These inhibitors will be tested in enzymatic, cellular and animal models. The M2 studies and inhibitor testing will be done in the applicant's laboratory. The Co-Investigator Dr Ghosh will do synthesis of inhibitors.