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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7783786
• 关键词: Affect; Affinity; Alzheimer' s Disease; Amino Acids; Biochemistry; Biological; Biological Assay; Biological Factors; Chemiluminescence assay; Chromatography; Complex Mixtures; Cyanobacterium; Disease Progression; Eligibility Determination; Evaluation; Exclusion; FDA approved; Goals; Link; Marines; Membrane; Natural Product Drug; Needles; Peptide Fragments; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Porifera; Protocols documentation; Research; Scheme; Screening procedure; Series; Solutions; Source; Staging; Structure; Testing; Therapeutic; Time; Veins; analog; base; beta-site APP cleaving enzyme 1; design; drug discovery; improved; inhibitor/antagonist; innovation; marine organism; neurotoxic; novel strategies; polypeptide; public health relevance; small molecule libraries; tool

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，并使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的工具的新化合物。鉴于缺乏任何FDA批准的对疾病进展有显著影响的药物疗法，这项研究的需求是巨大的。在这方面，该项目的具体目标是：1。开发一种创新的BACE 1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孔板中进行的荧光测定与LC-MS均相亲和测定串联组合。2.从蓝细菌和海绵中分离和结构表征在任一筛选试验中检测为阳性的新物质，以检验来自这些来源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BACE 1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渗透性和PgP相互作用，并根据需要进行进一步评价。公共卫生相关性：这项研究的长期目标是改进天然产物药物发现策略，并使用这些改进的策略来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的生物化学和生理学的工具的新化合物。鉴于缺乏任何FDA批准的药物治疗，对这项研究的需求是巨大的，这些药物治疗会显着影响疾病的进展。

项目成果

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.

Natural products as a source of Alzheimer's drug leads.

• DOI: 10.1039/c0np00027b
• 发表时间: 2011-01
• 期刊: Natural product reports
• 影响因子: 11.9
• 作者: Williams P;Sorribas A;Howes MJ
• 通讯作者: Howes MJ

Daedalols A-C, fungal-derived BACE1 inhibitors.

Daedalols A-C，真菌衍生的 BACE1 抑制剂。

• DOI: 10.1016/j.bmc.2011.09.029
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Sorribas,Analia;Jimenez,JorgeI;Yoshida,WesleyY;Williams,PhilipG
• 通讯作者: Williams,PhilipG

Xestosaprols from the Indonesian Marine Sponge Xestospongia sp.

• DOI: 10.1021/np100203x
• 发表时间: 2010-06-01
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Dai, Jingqiu;Sorribas, Analia;Williams, Philip G.
• 通讯作者: Williams, Philip G.