Inhibition of beta-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library.
Inhibition of beta-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library.
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DOI：
10.1006/jsbi.2000.4245
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发表时间：
2000-06
影响因子：
3
通讯作者：
N. Reixach;E. Crooks;J. Ostresh;R. Houghten;S. Blondelle
中科院分区：
文献类型：
--
作者：
N. Reixach;E. Crooks;J. Ostresh;R. Houghten;S. Blondelle
阿尔茨海默病是一种进行性神经变性疾病，其特征在于淀粉样蛋白纤维在脑中的存款，所述淀粉样蛋白纤维由β-淀粉样蛋白肽（Abeta）的自聚集聚合产生。有证据表明，Abeta在水溶液中形成稳定聚集体的能力与其神经毒性直接相关。Abeta的细胞毒性作用归因于与肽片段Abeta 25 -35对应的结构域的聚集性质。为了产生新型的Abeta神经毒性和/或聚集抑制剂，产生了由23 375个咪唑并吡啶并吲哚组成的基于混合物的合成组合文库，并筛选了Abeta 25 -35对大鼠嗜铬细胞瘤PC-12细胞系的神经毒性抑制。然后通过圆二色性（CD）和硫黄素-T荧光光谱法评价鉴定的先导化合物对A β 25 -35聚集的影响。还测定了它们对抗A β 1 -42对PC-12细胞系的神经毒性的活性。活性最高的咪唑并吡啶并吲哚在低至中等微摩尔范围内抑制A β 25 -35和A β 1 -42神经毒性。此外，通过CD和荧光光谱法观察到Abeta 25 -35的无规卷曲至β-折叠转变和自聚集的抑制，支持Abeta聚集过程的抑制与神经毒性之间的关系。
Alzheimer's disease is a progressive neurodegenerative disorder characterized by the deposit of amyloid fibrils in the brain that result from the self-aggregative polymerization of the beta-amyloid peptide (Abeta). Evidence of a direct correlation between the ability of Abeta to form stable aggregates in aqueous solution and its neurotoxicity has been reported. The cytotoxic effects of Abeta have been attributed to the aggregation properties of a domain corresponding to the peptide fragment Abeta25-35. In an effort to generate novel inhibitors of Abeta neurotoxicity and/or aggregation, a mixture-based synthetic combinatorial library composed of 23 375 imidazopyridoindoles was generated and screened for inhibition of Abeta25-35 neurotoxicity toward the rat pheochromocytoma PC-12 cell line. The effect of the identified lead compounds on Abeta25-35 aggregation was then evaluated by means of circular dichroism (CD) and thioflavin-T fluorescence spectroscopy. Their activity against Abeta1-42 neurotoxicity toward the PC-12 cell line was also determined. The most active imidazopyridoindoles inhibited both Abeta25-35 and Abeta1-42 neurotoxicity in the low- to mid-micromolar range. Furthermore, inhibition of the random coil to beta-sheet transition and self-aggregation of Abeta25-35 was observed by CD and fluorescence spectroscopy, supporting the relationship between inhibition of the Abeta aggregation process and neurotoxicity.