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: 7369682
• 负责人: DUY H HUA
• 金额: $ 26.1万
• 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/7369682
• 关键词: AP40; Adopted; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Animals; Binding; Biochemical; Blood - brain barrier anatomy; Brain; Brain Diseases; Buffers; Cells; Cerebrum; Cessation of life; Circular Dichroism; Class; Code; Condition; Cultured Cells; Dependence; Deposition; Development; Disease; Dose; Goals; Helix (Snails); Human; In Vitro; Label; Lead; Length; Lesion; Libraries; Maps; Metabolism; Methodology; Modeling; Mus; NMR Spectroscopy; Names; Neuroblastoma; Neurofibrillary Tangles; Neurons; Neuropil; Pathogenesis; Pathology; Patients; Penetration; Peptides; Pharmaceutical Preparations; Physiological; Positioning Attribute; Precipitation; Process; Property; Proteins; Pyrones; Research Personnel; Scheme; Screening procedure; Senile Plaques; Solubility; Staging; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Tg2576; Therapeutic; Toxic effect; Transgenic Mice; abeta accumulation; abeta oligomer; alpha helix; amyloid fibril formation; analog; beta pleated sheet; design; drug development; ear helix; extracellular; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; functional group; in vivo; neurotoxicity; prevent; programs; research study; size; stoichiometry

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.

阿尔茨海默氏病（AD）是一种进行性且不可逆的脑部疾病，没有已知的治愈方法。一个小 蛋白质，含有39-43个氨基酸的淀粉样β肽（ABETA）被广泛认为是罪魁祸首 疾病。最近的证据表明，Abeta的可溶性低聚物可能代表主要有毒物种 AD中的淀粉样蛋白。人们认为，新生产的Abeta是单体，可溶和无毒的，采用 正常生理条件下的随机线圈/α-螺旋混合物结构。在广告中，Abeta经历了 从随机线圈/α-螺旋到β-片结构的构象变化，导致寡聚和 沉淀。为了寻找阻断这种构象变化的化合物，我们发现一类 三环吡咯（TP），尤其是CP2（代码名称），可防止人类神经母细胞瘤MC65细胞的死亡 与含Abeta的代谢产物的细胞内积累有关。 CP2抑制Abeta 1-的聚集 40和abeta1-42肽，阻塞Abeta1-40和Abeta1-42β-42β-42型β-42肽，并与Abeta结合 体外肽。 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）研究 在存在CP2和类似物的情况下，Abeta40和Abeta42的结构变化和聚集状态； （2） 识别CP2阻塞Beta-theet形成和ABETA40和聚集的机制 Abeta42; （3）TP的小库的合成，C9，C11的CP2的新类似物 和C14; （4）研究细胞培养中CP2类似物的体外生物活性； （5）体内研究 CP2类似物与3XTG-AD APP小鼠的药理作用。该提议的最终目标是 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-肽的寡聚已被证明是 AD发病机理。单体ABETA是在正常代谢期间产生的，似乎没有有毒 对神经元的影响。但是，可溶性寡聚ABETA表现出高神经元毒性。抑制 这些有毒的可溶性Abe​​ta低聚物的形成将为AD提供治疗剂。