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

捕获抑制剂：发现分泌酶先导物的亲和方法

• 批准号: 8083931
• 负责人: Philip Williams
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8083931
• 关键词: Address; Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biochemical; Biological; Biological Assay; Biological Factors; Blood - brain barrier anatomy; Cade; Chemical Structure; Chemicals; Complement; Complex; Complex Mixtures; Data; Development; Disease; Disease Progression; Drug Delivery Systems; Eligibility Determination; Enzymes; Etiology; Evaluation; Goals; Impaired cognition; Industry; Lead; Libraries; Link; Marines; Medical; Oceans; Outcomes Research; P-Glycoprotein; Patients; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Production; Protocols documentation; Research; Screening procedure; Series; Solutions; Source; Therapeutic; Work; base; beta-site APP cleaving enzyme 1; chemical resource; cytotoxicity; design; drug development; drug discovery; inhibitor/antagonist; innovation; marine natural product; meetings; neurotoxic; novel; polypeptide; secretase; small molecule

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.

描述（由申请人提供）：淀粉样蛋白β的低聚物的形成是阿尔茨海默氏病发展的关键因素之一。可以有效抑制A2产生并因此减少聚集量的药物将使全球数百万患者受益。最终，访问与现有筛选库的补充的新型化学多样性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来源中发现可用于治疗阿尔茨海默氏病或​​作为生化探针的新药样小分子，以进一步了解这种疾病的发展。该提案的目的是我们追求该目标的下一步，是使用新的筛选协议来识别这些铅化合物，该方案将迅速将混合物中的特定化合物与观察到的生物学效应联系起来，而无需费力的生物测定。隔离（目标1）。严格的抑制剂生物学评估将确定最佳铅（AIM 2）。这种态度具有创新性，因为它解决了如何以新的方式将化学结构与活动联系起来的天然产物的基本障碍，并将这种解决方案应用于阿尔茨海默氏症的药物发现问题。该提案的具体目的是：1。使用创新方案鉴定2-分泌酶（BACE1）的抑制剂，该方案使用新的LC-MS同质亲和力测定法将混合物中的特定化合物与观察到的生物学活性迅速联系起来。 2。评估新抑制剂作为BACE1的潜力，使用旨在识别最佳候选者的测定法。我们期望确定结构前所未有的BACE1抑制剂类别。这些新的潜在抗阿尔茨海默氏药物铅将在一系列的生化测定中进行评估，以评估批评CNS药物开发的参数。满足这些要求的有限的化合物将与行业合作进行进一步研究。如果成功的话，新发现的铅将通过最终将BACE1验证为药物靶标，从而验证淀粉样蛋白酶假设，并为阿尔茨海默氏症患者提供迫切需要的治疗方法，从而产生积极影响。 公共卫生相关性：该提案是对针对酶Bace1的海洋独特化学资源的首次系统检查，该药物是酶Bace1，这对于阿尔茨海默氏病的发展至关重要。为了实现这一目标，该提案利用了我们最近开发的新筛选方案，该方案旨在将生物活性迅速将其与复杂混合物中的特定化学物联系起来。