Inhibition of Alzheimer's Beta-Amyloid Fibril Formation

抑制阿尔茨海默病β-淀粉样原纤维的形成

• 批准号: 7103269
• 负责人: DUY H HUA
• 金额: $ 28.54万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103269
• 关键词: Alzheimer' s disease; amyloid proteins; atomic force microscopy; biotechnology; conformation; cyclic compound; drug design /synthesis /production; drug discovery /isolation; genetically modified animals; heavy metals; laboratory mouse; neuropathology; neuropharmacology; neurotoxicology; nuclear magnetic resonance spectroscopy; peptide library; protein engineering; protein isoforms; protein protein interaction; protein purification; protein structure function; pyrones; stoichiometry; surface plasmon resonance; tissue /cell culture

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive and irreversible brain disorder with no known cure. A small protein, amyloid beta peptide (Abeta) containing 39-43 amino acids, is widely considered a culprit for the disease. Recent evidence indicates that soluble oligomers of Abeta may represent the primary toxic species of amyloid in AD. It is accepted that newly produced Abeta is monomeric, soluble and non-toxic, adopting random coil/alpha-helix mixture structures under normal physiological conditions. In AD, Abeta undergoes conformational changes from random coil/alpha-helix to beta-sheet structure, resulting in oligomerization and precipitation. In search of a compound that blocks this conformational change, we discovered that a class of tricyclic pyrones (TP), especially CP2 (code name), prevents the death of human neuroblastoma MC65 cells related to intracellular accumulation of Abeta-containing metabolites. CP2 inhibits the aggregation of Abeta 1- 40 and Abeta1-42 peptides, blocks Abeta1-40 and Abeta1-42 beta-sheet formation, and binds to Abeta peptides in vitro. CP2 also penetrated blood-brain barrier in mice. These exciting results suggest that CP2 may potentially serve as a drug to treat AD. We propose the following specific aims: (1) Studies of the structural changes and aggregation states of Abeta40 and Abeta42 in the presence of CP2 and analogs; (2) Identification of the mechanism by which CP2 blocks beta-sheet formation and aggregation of Abeta40 and Abeta42; (3) Syntheses of a small library of TP, new analogs of CP2 containing functional groups at C9, C11 and C14; (4) Studies of the in vitro bioactivities of CP2 analogs in cell cultures; and (5) Studies of the in vivo pharmacological effect of CP2 analogs with 3xTg-AD APP mice. The ultimate goal of this proposal are to identify a lead compound that is able to block the formation of Ab lesions in animal model, which may lead to drugs for the treatment of AD. CP2 and its analogs should have great potential in AD drug development. Relevance: Oligomerization of amyloid beta-peptide has been shown to be a major feature of the pathogenesis of AD. Monomeric Abeta is produced during normal metabolism and appears to have no toxic effects on neurons. However, soluble oligomeric Abeta showed high neuronal toxicity. Inhibition of the formation of these toxic soluble Abeta oligomers would provide therapeutics for AD.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性和不可逆的脑部疾病，目前尚无治愈方法。一种小蛋白质，淀粉样β肽（Abeta）含有39-43个氨基酸，被广泛认为是该疾病的罪魁祸首。最近的证据表明，可溶性低聚物的Abeta可能代表的主要有毒物质的淀粉样蛋白在AD。公认的是，新产生的Abeta是单体的、可溶的和无毒的，在正常生理条件下采用无规卷曲/α-螺旋混合物结构。在AD中，Abeta经历从无规卷曲/α-螺旋到β-折叠结构的构象变化，导致寡聚化和沉淀。在寻找阻断这种构象变化的化合物时，我们发现一类三环吡喃酮（TP），特别是CP 2（代号），可防止与含Abeta代谢物的细胞内积累相关的人神经母细胞瘤MC 65细胞死亡。CP 2抑制Abeta 1- 40和Abeta 1 -42肽的聚集，阻断Abeta 1 -40和Abeta 1 -42 β-折叠形成，并在体外与Abeta肽结合。CP 2也能穿透小鼠血脑屏障。这些令人兴奋的结果表明，CP 2可能作为治疗AD的药物。我们提出了以下具体目标：（1）研究CP 2及其类似物存在下A β 40和A β 42的结构变化和聚集状态：（2）鉴定CP 2阻断A β 40和A β 42的β折叠形成和聚集的机制;（3）CP_2的C_9、C_11和C_14位功能基团的TP类似物的小型库的合成：（4）CP_2类似物在细胞培养中的体外生物活性研究;（5）用3xTg-AD APP小鼠研究CP 2类似物的体内药理作用。本提案的最终目标是鉴定能够在动物模型中阻断Ab病变形成的先导化合物，这可能导致用于治疗AD的药物。CP 2及其类似物在AD药物开发中具有巨大的潜力。 相关性：淀粉样β肽的寡聚化已被证明是AD发病机制的主要特征。单体Abeta在正常代谢过程中产生，似乎对神经元没有毒性作用。然而，可溶性寡聚Abeta显示出高神经元毒性。抑制这些毒性可溶性Abeta寡聚体的形成将为AD提供治疗剂。