Mechanism of Amyloid Inhibition by Small Molecules

小分子抑制淀粉样蛋白的机制

• 批准号: 7474647
• 负责人: Joshua A Kritzer
• 金额: $ 5.04万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474647
• 关键词: Amyloid; Amyloid fibers; Amyloidosis; Antibody Binding Sites; Binding; Binding Sites; Biological Assay; Biotin; Cataloging; Catalogs; Chemicals; Collection; Congo Red; Data; Disulfides; Epitope Mapping; Fiber; Goals; Label; Modeling; Molecular; Peptides; Prevention; Proteins; Purpose; Range; Research Proposals; Research Training; Site; Structural Models; Structure-Activity Relationship; Sulfhydryl Compounds; Techniques; Validation; Variant; aggregation pathway; amyloid formation; analog; base; crosslink; data modeling; drug discovery; inhibitor/antagonist; monomer; prevent; research study; small molecule

DESCRIPTION (provided by applicant): The primary goal of this research proposal is to derive a model for the activity of small molecule amyloid inhibitors. Data for this model will be collected in three parallel but related approaches, which take advantage of the well-characterized amyloidogenic protein NM. The first approach will detail the structure-activity relationships, which govern inhibition of amyloid formation by the small molecules Congo Red (CR) and 4,5- dianilinophthalimide (DAPH) and their analogues, cataloguing what chemical aspects of these molecules contribute to their potency. The second approach will establish the molecular mechanism by which CR and DAPH prevent NM aggregation by investigating their effects on specific steps in the NM aggregation pathway. The third approach will identify the binding sites of small molecule NM inhibitors using epitope mapping and cross-linking experiments with functionalized CR and DAPH analogues. The data collected in these approaches will inform a detailed mechanistic and structural model for the inhibition of NM aggregation and fiber formation. A precise model of how small molecules bind to NM and inhibit its aggregation will be a critical first step in understanding the molecular basis of amyloid inhibition by small molecules.

描述（由申请人提供）：该研究建议的主要目标是为小分子淀粉样蛋白抑制剂的活性提供模型。该模型的数据将以三种平行但相关的方法收集，这些方法利用了特征良好的淀粉样蛋白蛋白NM。第一种方法将详细介绍结构活性关系，该关系由小分子刚果红（CR）和4,5-二甲二甲酰亚胺（DAPH）及其类似物抑制淀粉样蛋白形成，并分解这些分子的化学方面有助于其效力。第二种方法将建立CR和DAPH通过研究NM聚集途径中特定步骤的影响来阻止NM聚集的分子机制。第三种方法将使用具有功能化的CR和DAPH类似物的表位映射和交联实验来鉴定小分子NM抑制剂的结合位点。这些方法中收集的数据将为抑制NM聚集和纤维形成的详细机械和结构模型提供信息。小分子如何与NM结合并抑制其聚集的精确模型将是理解小分子淀粉样蛋白抑制的分子基础的关键第一步。

项目成果

Yeast can accommodate phosphotyrosine: v-Src toxicity in yeast arises from a single disrupted pathway.

酵母可以容纳磷酸酪氨酸：酵母中的 v-Src 毒性来自于单一被破坏的途径。

• DOI: 10.1093/femsyr/foy027
• 发表时间: 2018
• 期刊: FEMS yeast research
• 影响因子: 3.2
• 作者: Kritzer,JoshuaA;Freyzon,Yelena;Lindquist,Susan
• 通讯作者: Lindquist,Susan