Mechanism of Amyloid Inhibition by Small Molecules

描述（由申请人提供）：本研究提案的主要目标是推导小分子淀粉样蛋白抑制剂活性的模型。该模型的数据将收集在三个平行的，但相关的方法，这利用了良好的特点，淀粉样蛋白NM。第一种方法将详细说明结构-活性关系，这决定了小分子刚果红（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，编目这些分子的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防止NM聚集的分子机制。第三种方法将使用表位作图和与官能化CR和DAPH类似物的交联实验来鉴定小分子NM抑制剂的结合位点。在这些方法中收集的数据将通知详细的机制和结构模型的抑制NM聚集和纤维形成。小分子如何结合到NM和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.