DEVELOPMENT OF AMYLOID B-PROTEIN OLIGOMERIZATION INHIBITORS

B 淀粉样蛋白寡聚化抑制剂的开发

• 批准号: 8114005
• 负责人: GAL BITAN
• 金额: $ 26.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8114005
• 关键词: Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Back; Biological; Biological Assay; C-terminal; Cell Line; Characteristics; Circular Dichroism; Clinical; Collaborations; Data; Development; Experimental Models; Future; Goals; Knowledge; Laboratories; Length; Life; Ligands; Link; Mass Spectrum Analysis; Modification; Molecular Conformation; Neurons; Pattern; Peptides; Preparation; Process; Proteins; Proteolysis; Relative (related person); Resolution; Role; Screening procedure; Side; Silicon Dioxide; Solubility; Solutions; Spectrum Analysis; Structure; Structure-Activity Relationship; Surface; Testing; Toxic effect; abeta oligomer; aqueous; base; crosslink; design; enzyme substrate; feeding; flexibility; inhibitor/antagonist; ion mobility; member; neurotoxic; neurotoxicity; novel; prevent; programs; receptor; three dimensional structure

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.

我们假设可溶性淀粉样β蛋白（Abeta）寡聚体是神经毒性的关键效应物， 可能是阿尔茨海默病（AD）的主要原因。因此，抑制Abeta寡聚化 是预防和治疗AD的有吸引力的策略。我们建议使用一个系统的，理性的 设计方法，用于制备和结构活性研究的Abeta寡聚化抑制剂。我们 将集中我们的努力在早期Abeta（1-42）寡聚体的抑制剂称为“副核”。“我们选择早 Abeta（1-42）寡聚体作为我们的主要靶点，因为Abeta（1-42）特别与AD相关， 抑制Abeta（1-42）的早期组装将减轻神经毒性作用，这两种寡聚体 它们本身和较大的神经毒性组件，原纤维和原纤维，其中副核是 前体我们的设计基于最近的实验和建模数据， 副核组装的特征，包括一级-四级结构关系， Abeta（1-42）的C-末端的构象。该区域直接负责加强 相对于更丰富的同种异型物， Abeta（1-40）。抑制剂设计过程与结构和生物项目紧密结合 在整个方案中。设计过程不仅将受益于结构数据 由计划成员产生，但也将反馈到结构研究，并提供 进一步了解Abeta中的特定区域和残基如何相互作用以形成 低聚物