Capture the Inhibitor: Affinity Approaches to the Discovery of Secretase Leads

描述（由申请人提供）：根据淀粉样蛋白级联假说，淀粉样蛋白低聚物的形成是阿尔茨海默病发展的关键因素之一。能够有效抑制A2生成从而减少聚集量的药物将使全世界数百万患者受益。最终，获取新的化学多样性，补充现有的筛选库，可能是解锁这些治疗方法的关键。因此，我们的长期目标是从海洋资源中发现新的类似药物的小分子，可用于治疗阿尔茨海默病或作为生化探针，以进一步了解这种疾病的发展。本提案的目标，也是我们追求这一目标的下一步，是使用一种新的筛选方案来识别这些先导化合物，该方案将迅速将混合物中的特定化合物与观察到的生物效应联系起来，而不需要费力的生物测定指导分离（目标1）。对抑制剂进行严格的生物学评估将确定最佳先导（目标2）。这个提议是创新的，因为它解决了天然产物中如何以一种新的方式将化学结构与活性联系起来的基本障碍，并将这种解决方案应用于阿尔茨海默病药物发现问题。该提案的具体目标是：1。使用一种创新的方案来鉴定2-分泌酶（BACE1）的抑制剂，该方案使用新的LC-MS均相亲和试验将混合物中的特定化合物与观察到的生物活性快速联系起来。2. 评估新抑制剂作为BACE1引线的潜力，使用一系列旨在确定最佳候选药物的试验。我们期望鉴定出结构上前所未有的BACE1抑制剂。这些新类别的潜在抗阿尔茨海默病药物先导将在一系列生化分析中进行评估，以评估对中枢神经系统药物开发至关重要的参数。满足这些要求的有限数量的化合物将与工业界合作进行进一步的研究。如果成功，新发现的线索有望通过最终验证BACE1作为药物靶点，验证淀粉样蛋白cade假说并为阿尔茨海默病患者提供急需的治疗方法而产生积极影响。

DESCRIPTION (provided by applicant): The formation of oligomers of amyloid-beta is one of the critical factors in the development of Alzheimer's disease, according to the Amyloid Cascade Hypothesis. Drugs that can effectively inhibit A2 production and thus reduce the amount of aggregation would benefit millions of patients world-wide. Ultimately, accessing novel chemical diversity, which complements existing screening libraries, may be the key to unlocking these treatments. Our long-term goal therefore is to discover new drug-like small molecules from marine sources that can be used for the treatment of Alzheimer's disease or as biochemical probes to further our under- standing of the development of this disorder. The objective of this proposal, which is our next step in pursuit of that goal, is to identify these lead compounds using a new screening protocol that will rapidly link a spe- cific compound in a mixture to the observed biological effect without requiring laborious bioassay guided isolation (Aim 1). Rigorous biological evaluation of the inhibitors will identify the best lead (Aim 2). This pro- posal is innovative because it addresses the fundamental barrier in natural products of how to link chemical structure to activity in a new way and applies this solution to the problem of Alzheimer's drug discovery. The specific aims of the proposal are: 1. To identify inhibitors of 2-secretase (BACE1) using an innovative protocol that rapidly links a specific compound within a mixture to the observed biological activity using a new LC-MS homogenous affinity assay. 2. To evaluate the potential of the new inhibitors as BACE1 leads using a gauntlet of assays designed to identify the best candidate. We expect to identify structurally unprecedented classes of BACE1 inhibitors. These new classes of poten- tial anti-Alzheimer drug leads will be evaluated in a series of biochemical assays to assess parameters criti- cal to CNS drug development. A limited number of compounds that meet these requirements will be ad- vanced to further studies in partnership with industry. If successful, the newly discovered leads are ex- pected to have a positive impact by finally validating BACE1 as a drug target, validating the Amyloid Cas- cade Hypothesis and providing desperately needed therapeutics for Alzheimer's patients. PUBLIC HEALTH RELEVANCE: This proposal is the first systematic examination of the ocean's unique chemical resources for drug leads that target the enzyme BACE1, which is central to the development of Alzheimer's disease. To accomplish this goal, the proposal leverages a new screening protocol that we recently developed, which is designed to rapidly link biological activity to a specific chemical in a complex mixture.