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）：阿尔茨海默氏病（AD）是一种进行性且不可逆转的脑疾病，没有已知的治愈方法。一种小蛋白质，含39-43个氨基酸的淀粉样β肽（ABETA）被广泛认为是该疾病的罪魁祸首。最近的证据表明，Abeta的可溶性低聚物可能代表AD中淀粉样蛋白的主要有毒物种。可以接受的是，新生产的Abeta是单体，可溶性和无毒的，在正常生理条件下采用随机线圈/α-螺旋混合物结构。在AD中，Abeta经历了从随机线圈/α-螺旋变为β-片结构的构象变化，从而导致低聚和沉淀。为了寻找阻断这种构象变化的化合物，我们发现一类三轮吡咯（TP），尤其是CP2（代码名称），可以防止人类神经细胞瘤MC65细胞的死亡与含Abeta含Abeta的代谢物的细胞内积累相关的死亡。 CP2抑制Abeta 1-40和Abeta1-42肽的聚集，阻断Abeta1-40和Abeta1-42β-42β-42β-42β-42β-42β-42β-42肽，并在体外与Abeta肽结合。 CP2还穿透小鼠的血脑屏障。这些令人兴奋的结果表明，CP2可能有可能用作治疗AD的药物。我们提出以下具体目的：（1）在存在CP2和类似物的情况下，研究Abeta40和Abeta42的结构变化和聚集状态； （2）识别CP2阻塞β-曲面形成和Abeta40和Abeta42的聚集机制； （3）TP的小库的合成，即C9，C11和C14的CP2的新类似物； （4）研究细胞培养中CP2类似物的体外生物活性； （5）研究与3XTG-AD APP小鼠的CP2类似物的体内药理作用。该提案的最终目标是确定能够阻止动物模型中AB病变形成的铅化合物，这可能会导致用于治疗AD的药物。 CP2及其类似物在AD药物开发中应该具有很大的潜力。 相关性：淀粉样β-肽的寡聚化已被证明是AD发病机理的主要特征。单体ABETA是在正常代谢期间产生的，似乎对神经元没有毒性作用。但是，可溶性寡聚ABETA表现出高神经元毒性。抑制这些有毒可溶性Abe​​ta低聚物的形成将为AD提供治疗剂。