A Needle in a Haystack: New approaches to Alzheimer's Drug Discovery from Natural

描述（由申请人提供）：本研究的长期目标是改进天然产物药物发现策略，并利用这些改进的策略发现有可能用于治疗阿尔茨海默病或作为研究阿尔茨海默病生物化学和生理学工具的新化合物。鉴于缺乏任何FDA批准的对疾病进展有显著影响的药物治疗，这项研究的必要性是巨大的。在这方面，这个项目的具体目标是：1。开发一种创新的BACE1筛选方案，首次将混合物中的单一化合物与观察到的生物活性快速联系起来。该方案结合了化学发光测定，在96孔板上进行，串联LC-MS均相亲和测定。2. 从蓝藻菌和海绵中分离新物质并对其进行结构表征，以验证从这些来源中提取的天然产物是阿尔茨海默病药物线索的合理来源的假设。3. 评价这些化合物作为潜在的BACE1抑制剂。化合物将首先检查其效力、细胞活性、神经保护作用、血脑屏障通透性和PgP相互作用，并根据需要进行进一步的评估。公共卫生相关性：本研究的长期目标是改进天然产物药物发现策略，并利用这些改进的策略发现有可能用于治疗阿尔茨海默病或作为研究阿尔茨海默病生物化学和生理学工具的新化合物。鉴于缺乏任何FDA批准的能显著影响疾病进展的药物治疗，这项研究的必要性是巨大的。

DESCRIPTION (provided by applicant): The long-term objectives of this research are to improve natural product drug discovery strategies and to use these improved strategies to discover new compounds that have the potential to be useful in treating Alzheimer's disease or as a tool for studying the biochemistry and physiology of Alzheimer's disease. The need for this research is substantial given the lack of any FDA approved drug therapies that have a significant effect on the progression of the disease. In that vein, the specific goals of this project are: 1. To develop an innovative BACE1 screening protocol that, for the first time, rapidly links a single compound within a mixture to the observed biological activity. This protocol combines a chemiluminescent assay, performed in 96-well plates, in series with a LC-MS homogeneous affinity assay. 2. To isolate and structurally characterize new substances from cyanobacteria and sponges testing positive in either screening assay, in order to test the hypothesis that natural products derived from these sources are a rational source of Alzheimer's drug leads. 3. To evaluate these compounds as potential BACE1 inhibitors. Compounds will be initially examined for potency, cellular activity, neuroprotective effect, BBB permeability, and PgP interactions with further evaluations conducted as warranted. PUBLIC HEALTH RELEVANCE: The long-term objectives of this research are to improve natural product drug discovery strategies and to use these improved strategies to discover new compounds that have the potential to be useful in treating Alzheimer's disease or as a tool for studying the biochemistry and physiology of Alzheimer's disease. The need for this research is substantial given the lack of any FDA approved drug therapies that significantly affect the progression of the disease.