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: 7596397
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596397
• 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; Cell Culture Techniques; Cells; Cerebrum; Cessation of life; Circular Dichroism; Code; Dependence; Deposition; Development; Disease; Dose; Goals; 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; extracellular; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; functional group; in vivo; neurotoxicity; prevent; programs; research study; 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.

阿尔茨海默病 (AD) 是一种进行性且不可逆转的脑部疾病，目前尚无治愈方法。一个小 β 淀粉样蛋白肽 (Abeta) 含有 39-43 个氨基酸，被广泛认为是导致 疾病。最近的证据表明，Abeta 的可溶性低聚物可能代表主要的有毒物质 AD 中的淀粉样蛋白。公认新生产的Abeta是单体、可溶且无毒的，采用 正常生理条件下的无规卷曲/α-螺旋混合物结构。在AD中，阿贝塔经历了 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。在寻找阻止这种构象变化的化合物时，我们发现了一类 三环吡喃酮 (TP)，尤其是 CP2（代号），可防止人神经母细胞瘤 MC65 细胞死亡 与含 Abeta 的代谢物的细胞内积累有关。 CP2 抑制 Abeta 1- 的聚集 40 和 Abeta1-42 肽，阻断 Abeta1-40 和 Abeta1-42 β-折叠形成，并与 Abeta 结合 体外肽。 CP2 还可以穿透小鼠的血脑屏障。这些令人兴奋的结果表明 CP2 可能作为治疗 AD 的药物。我们提出以下具体目标：（1）研究 CP2 及其类似物存在下 Abeta40 和 Abeta42 的结构变化和聚集状态； (2) 鉴定 CP2 阻断 Abeta40 和 Abeta-sheet 形成和聚集的机制 Abeta42； (3) TP小文库的合成，CP2的新类似物在C9、C11处含有官能团 和C14； (4) CP2类似物在细胞培养物中的体外生物活性研究； (5) 体内研究 CP2类似物对3xTg-AD APP小鼠的药理作用。该提案的最终目标是 鉴定出一种能够阻止动物模型中抗体损伤形成的先导化合物，这可能会导致 治疗 AD 的药物。 CP2及其类似物在AD药物开发中应该具有巨大的潜力。 相关性：β-淀粉样蛋白肽的寡聚化已被证明是 AD的发病机制。单体 Abeta 在正常代谢过程中产生，似乎没有毒性 对神经元的影响。然而，可溶性寡聚 Abeta 显示出高神经元毒性。抑制 这些有毒的可溶性 Abeta 寡聚物的形成将为 AD 提供治疗方法。

项目成果

Total syntheses of (+/-)-ovalicin, C4(S *)-isomer, and its C5-analogs and anti-trypanosomal activities.

(i-)-卵黄素、C4(S *)-异构体及其 C5-类似物的全合成和抗锥虫活性。

• 发表时间: 2008-05-01
• 影响因子: 3.5
• 作者: Hua, Duy H;Zhao, Huiping;Battina, Srinivas K;Lou, Kaiyan;Jimenez, Ana L;Desper, John;Perchellet, Elisabeth M;Perchellet, Jean;Chiang, Peter K
• 通讯作者: Chiang, Peter K

Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-beta peptide and neuronal cell interactions.

单细胞力学为探测淀粉样β肽和神经元细胞的相互作用提供了灵敏且定量的方法。

• 发表时间: 2010-08-03
• 影响因子: 11.1
• 作者: Lulevich, Valentin;Zimmer, Christopher C;Hong, Hyun;Jin, Lee;Liu, Gang
• 通讯作者: Liu, Gang

Amyloid β1-42 oligomer inhibits myelin sheet formation in vitro.

淀粉样β1-42 寡聚体抑制体外髓磷脂片的形成。

• 发表时间: 2012-03
• 影响因子: 4.2
• 作者: Horiuchi, Makoto;Maezawa, Izumi;Itoh, Aki;Wakayama, Kouji;Jin, Lee;Itoh, Takayuki;Decarli, Charles
• 通讯作者: Decarli, Charles

Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Abeta oligomer-induced cytotoxicity.

结合快速 MTT 甲臜胞吐作用测定和 MC65 保护测定，发现咔唑类似物可作为 Abeta 寡聚物诱导的细胞毒性的小分子抑制剂。

• 发表时间: 2007-01-26
• 影响因子: 2.9
• 作者: Hong, Hyun;Maezawa, Izumi;Yao, Nianhuan;Xu, Bailing;Diaz;Rana, Sandeep;Hua, Duy H;Cheng, R Holland;Lam, Kit S;Jin, Lee
• 通讯作者: Jin, Lee

Design, synthesis, and evaluation of bioactive small molecules.

生物活性小分子的设计、合成和评估。

• 发表时间: 2013-02
• 作者: Hua; Duy H
• 通讯作者: Duy H