SECRETASE ASSAYS TO DISCOVER DRUGS TO TREAT ALZHEIMER'S

描述：(逐字摘自申请者摘要)阿尔茨海默病(AD) 是一种涉及严重认知障碍的衰弱精神障碍。完毕 1000万人患有AD，给社会造成了3500亿美元的损失。一种可以 有效的乳头AD将价值500亿美元。目前，没有 有效治疗阿尔茨海默病。阿尔茨海默病的神经病理涉及斑块形成 在大脑和神经元死亡中。这些损伤被认为是由 神经毒剂β-肽，它是从一种蛋白质水解物中提取出来的 多肽前体，淀粉样前体蛋白(APP)。产生了β-肽 被称为分泌酶的蛋白酶从APP中释放出来。分泌酶活性的抑制剂和 β-肽的产生可能会阻止疾病的进展和 认知功能障碍，但这种抑制剂还没有开发出来，因为 目前还没有确定真正的分泌物。薇薇安·胡克博士，顾问 合作者们已经发现了能够自然产生 β-肽，并发现这些细胞的亚细胞器含有 真正的秘密。这些细胞器可以被提纯，这样只有 在其他细胞隔间中不相关的蛋白分解活性可能是 减少了。PI和他的同事已经开发出一种高灵敏度的荧光 利用这些细胞器和多肽底物的裂解物进行分泌酶测定 包含用于测量β-和γ-分泌酶的分泌酶识别位点 活动。在这项提案中，他们将开发和优化这些化验方法，以 实现灵敏、可重现和快速的分泌酶分析，使 在未来组合文库高通量筛选中的应用 发现抑制β-肽产生的化合物。这 该项目还将测试商业上可用的蛋白酶抑制剂，以 证明这种分泌酶分析可以有效地检测到抑制剂，以及 评估β-和伽马-分泌酶活性是否代表相似或 不同的药物靶点。这些可靠的分泌酶检测对于 开发改善AD患者心理健康的药物。 建议的商业应用：不可用

DESCRIPTION: (Verbatim from the Applicant's Abstract) Alzheimer's Disease (AD) is a debilitating mental disorder involving severe cognitive impairment. Over 10 million people have AD, costing society $350 billion. A drug that could effectively teat AD would be worth $50 billion. Presently, there is no effective treatment of AD. The neuropathology of AD involves plaque formation in the brain and neuronal death. The lesions are believed to be caused by the neurotoxic agent beta-peptide which is proteolytically derived from a polypeptide precusor, amyloid precusor protein (APP). Beta-peptide is produced from APP by proteases known as secretases. Inhibitors of secretase activity and beta-peptide production could block the progression of the disease and the cognitive dysfunctions, but such inhibitors have not been developed because authentic secretases have not been identified. Dr. Vivian Hook, the consultant of the project, and collaborators have discovered cells that naturally produce beta-peptide, and found that subcellular organelles from these cells contain the authentic secretases. These organelles can be purified so that only irrelevant proteolytic activities in other cellular compartments can be reduced. The PI and coworkers have developed a highly sensitive fluorescent secretase assay using the lysate of such organelles and peptide substrates containing the secretase recognition sites to measure beta- and gamma secretase activities. In this proposal, they will develop and optimize these assays to achieve sensitive, reproducible, and rapid secretase assays that will allow use of theses assays in future high throughput screening of combinatorial libraries for the discovery of compounds that inhibit beta-peptide production. This project will also test commercially available protease inhibitors to demonstrate that such secreatase assays can effectively detect inhibitors, and to assess whether beta- and gamma-secretase activities may represent similar or distinct drug targets. These authentic secretase assays will be essential for development of drugs to improve the mental health of AD patients. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE