Mechanism of Amyloid Inhibition by Small Molecules

小分子抑制淀粉样蛋白的机制

• 批准号: 7454964
• 负责人: Joshua A Kritzer
• 金额: $ 4.88万
• 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/7454964
• 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）：本研究计划的主要目标是建立小分子淀粉样蛋白抑制剂活性的模型。该模型的数据将通过三种平行但相关的方法收集，这些方法利用了充分表征的淀粉样蛋白 NM。第一种方法将详细说明结构-活性关系，该关系控制小分子刚果红 (CR) 和 4,5-二苯胺邻苯二甲酰亚胺 (DAPH) 及其类似物对淀粉样蛋白形成的抑制，并列出这些分子的哪些化学方面对其效力有贡献。第二种方法将通过研究 CR 和 DAPH 对 NM 聚集途径中特定步骤的影响来建立 CR 和 DAPH 阻止 NM 聚集的分子机制。第三种方法将使用表位作图和功能化 CR 和 DAPH 类似物的交联实验来识别小分子 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制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了解小分子抑制淀粉样蛋白的分子基础的关键的第一步。