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

大海捞针：从自然中发现阿尔茨海默病药物的新方法

基本信息

批准号：
7783786
负责人：
Philip Williams
金额：
$ 16.76万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

项目摘要

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.

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来发现有潜力用于治疗阿尔茨海默病或作为研究工具的新化合物阿尔茨海默病的生物化学和生理学。鉴于缺乏 FDA 批准的任何对疾病进展有显着影响的药物疗法，这项研究的需求是巨大的。本着这一精神，该项目的具体目标是： 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。该方案将在 96 孔板中进行的化学发光测定与 LC-MS 均相亲和力测定串联起来。 2. 从在任一筛选试验中检测呈阳性的蓝细菌和海绵中分离出新物质并进行结构表征，以检验源自这些来源的天然产物是阿尔茨海默病药物先导物的合理来源的假设。 3.评估这些化合物作为潜在的BACE1抑制剂。将首先检查化合物的效力、细胞活性、神经保护作用、BBB 通透性和 PgP 相互作用，并根据需要进行进一步评估。公共健康相关性：这项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来发现有潜力用于治疗阿尔茨海默病或作为研究生物化学和药物的工具的新化合物。阿尔茨海默病的生理学。鉴于缺乏 FDA 批准的任何显着影响疾病进展的药物疗法，这项研究的需求是巨大的。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isoflavonoids from Ficus benjamina and their inhibitory activity on BACE1.

DOI：
10.1055/s-0032-1315001
发表时间：
2012-08
期刊：
Planta medica
影响因子：
2.7
作者：
Dai J;Shen D;Yoshida WY;Parrish SM;Williams PG
通讯作者：
Williams PG

Stictamides A-C, MMP12 inhibitors containing 4-amino-3-hydroxy-5-phenylpentanoic acid subunits.

DOI：
10.1021/jo200241h
发表时间：
2011-05-20
期刊：
JOURNAL OF ORGANIC CHEMISTRY
影响因子：
3.6
作者：
Liang, Zhibin;Sorribas, Analia;Sulzmaier, Florian J.;Jimenez, Jorge I.;Wang, Xin;Sauvage, Thomas;Yoshida, Wesley Y.;Wang, Guangyi;Ramos, Joe W.;Williams, Philip G.
通讯作者：
Williams, Philip G.

Daedalols A-C, fungal-derived BACE1 inhibitors.

Daedalols A-C，真菌衍生的 BACE1 抑制剂。