DEVELOPMENT OF AMYLOID B-PROTEIN OLIGOMERIZATION INHIBITORS

我们假设，可溶性淀粉样β蛋白(Abeta)寡聚体是神经毒性和 可能是阿尔茨海默病(AD)的主要原因。因此，抑制Aβ齐聚 是预防和治疗阿尔茨海默病的一个有吸引力的策略。我们建议使用系统的、理性的 Aβ齐聚抑制剂的制备及构效关系研究的设计方法。我们 将把我们的工作重点放在被称为“副核”的早期Abeta(1-42)寡聚体的抑制剂上。我们很早就选择 我们的主要目标是Abeta(1-42)低聚物，因为Abeta(1-42)与AD特别相关，而且因为 抑制Abeta(1-42)的早期组装将减轻这两种寡聚体的神经毒性效应 以及更大的神经毒性组件，原纤维和纤维，对它们来说，核旁是 先驱物。我们的设计基于最近的实验和建模数据，这些数据描绘了结构 核旁组装的特征，包括初级-四级结构关系和 Abeta(1-42)C-末端的构象。该区域直接负责增强的 相对于更丰富的异构体，Abeta(1-42)的毒性和独特的齐聚模式， Abeta(1-40)。缓蚀剂的设计过程与结构和生物项目紧密结合 在整个计划中。设计过程不仅将受益于结构数据 由计划成员生成，但也将反馈到结构研究中并提供 进一步了解Abeta中特定区域和残基是如何相互作用形成的 齐聚物。

We hypothesize that soluble amyloid beta-protein (Abeta) oligomers are key effectors of neurotoxicity and may be a primary cause of Alzheimer's disease (AD). Consequently, inhibition of Abeta Oligomerization is an attractive strategy for preventing and treating AD. We propose to use a systematic, rational design approach for preparation and structure-activity studies of Abeta Oligomerization inhibitors. We will focus our efforts on inhibitors of early Abeta(1-42) oligomers termed "paranuclei." We choose early Abeta(1-42) oligomers as our primary target because Abeta(1-42) is particularly linked to AD and because inhibition of early assembly of Abeta(1-42) will alleviate the neurotoxic effects, both of the oligomers themselves and of the larger neurotoxic assemblies, protofibrils and fibrils, for which paranuclei are precursors. Our design in based on recent experimental and modeling data that delineate structural features of paranucleus assembly, including primary-quaternary structure relationships and conformation of the C-terminus of Abeta(1-42). This region is responsible directly for the enhanced toxicity and distinct Oligomerization pattern of Abeta(1-42) relative to the more abundant alloform, Abeta(1-40). The inhibitor design process is tightly integrated with the structural and biological projects within the overall Program. The design process not only will benefit from the structural data generated by the Program members, but also will feed back into structural studies and provide further understanding of how particular regions and residues in Abeta interact with each other to form oligomers.