Mechanism 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推导出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，这些方法利用了表征良好的淀粉样蛋白NM。第一种方法将详细描述结构-活性关系，这些结构-活性关系控制着小分子刚果红（CR）和4,5-二苯酞酰亚胺（DAPH）及其类似物对淀粉样蛋白形成的抑制，并对这些分子的化学方面的作用进行分类。第二种方法将通过研究CR和DAPH对纳米聚集途径中特定步骤的影响，建立CR和DAPH阻止纳米聚集的分子机制。第三种方法将通过表位定位和与功能化的CR和DAPH类似物的交联实验来确定小分子NM抑制剂的结合位点。在这些方法中收集的数据将为NM聚集和纤维形成的抑制提供详细的机制和结构模型。一个精确的小分子如何与纳米结合并抑制其聚集的模型将是理解小分子抑制淀粉样蛋白的分子基础的关键的第一步。

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.