Mechanism of Amyloid Inhibition by Small Molecules

描述(由申请人提供)：这项研究提案的主要目标是推导出小分子淀粉样蛋白抑制剂的活性模型。这个模型的数据将通过三种平行但相关的方法收集，这三种方法利用了具有良好特征的淀粉样蛋白NM。第一种方法将详细说明结构-活性关系，这种关系支配着小分子刚果红(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作用，并对这些分子的哪些化学方面对其效力做出了贡献。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。第三种方法将利用表位映射和与官能化的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。通过这些方法收集的数据将为抑制NM聚集和纤维形成提供详细的机理和结构模型。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抑制淀粉样蛋白的分子基础的关键第一步。

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.