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: 7663803
• 负责人: GAL BITAN
• 金额: $ 25.38万
• 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/7663803
• 关键词: Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Back; Biological; Biological Assay; C-terminal; Cell Line; Characteristics; Circular Dichroism; Classification; 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; Spectrometry; Structure; Structure-Activity Relationship; Surface; Testing; Toxic effect; abeta oligomer; aqueous; base; crosslink; data modeling; design; enzyme substrate; feeding; 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蛋白（Abeta）低聚物是神经毒性和神经毒性的关键效应物