Novel oxindole compounds inhibit the aggregation of amyloidogenic proteins associated with neurodegenerative diseases
Novel oxindole compounds inhibit the aggregation of amyloidogenic proteins associated with neurodegenerative diseases
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DOI：
10.1016/j.bbagen.2022.130114
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发表时间：
2022-02-26
影响因子：
3
通讯作者：
Kamatari, Yuji O.
中科院分区：
文献类型：
--
作者：
Kimura, Shintaro;Kamishina, Hiroaki;Kamatari, Yuji O.
淀粉样蛋白在细胞中形成聚集体，从而导致神经退行性疾病，包括阿尔茨海默氏症和朊病毒病，人类的肌萎缩侧索硬化症（ALS），以及狗的退行性脊髓病（DM）和认知功能障碍。因此，许多小分子化合物已被筛选以检验其对淀粉样蛋白聚集的抑制作用。然而，尚未发现适合过渡到临床使用的有效药物。在这里，我们使用硫黄素- t荧光检测了几种新的氧化吲哚化合物（GIF化合物）对犬突变体超氧化物歧化酶1 （cSOD1 E40K）聚集形成的抑制作用，cSOD1 E40K是导致糖尿病的致病突变。大多数GIF化合物抑制cSOD1 E40K的聚集。其中，GIF-0854-r和GIF-0890-r最有效。在转染cSOD1 e40k的细胞中也观察到它们的抑制作用。此外，GIF-0890-r有效地抑制了ALS致病突变人类SOD1 G93A的聚集形成。GIF-0827-r和GIF-0856-r也能有效抑制人朊病毒蛋白（hPrP）的聚集形成。随后，它们对cSOD1和hPrP聚集的抑制作用之间的相关性被证明，表明GIF化合物抑制多种淀粉样蛋白的聚集形成。总之，新的氧化多酚化合物（GIF-0827-r, GIF-0854-r， GIF-0856-r和GIF-0890-r）被认为是淀粉样变性神经退行性疾病的有用治疗候选者。
Amyloidogenic proteins form aggregates in cells, thereby leading to neurodegenerative disorders, including Alzheimer's and prion's disease, amyotrophic lateral sclerosis (ALS) in humans, and degenerative myelopathy (DM) and cognitive dysfunction in dogs. Hence, many small-molecule compounds have been screened to examine their inhibitory effects on amyloidogenic protein aggregation. However, no effective drug suitable for transition to clinical use has been found. Here we examined several novel oxindole compounds (GIF compounds) for their inhibitory effects on aggregate formation of the canine mutant superoxide dismutase 1 (cSOD1 E40K), a causative mutation resulting in DM, using Thioflavin-T fluorescence. Most GIF compounds inhibited the aggregation of cSOD1 E40K. Among the compounds, GIF-0854-r and GIF-0890-r were most effective. Their inhibitory effects were also observed in cSOD1 E40K-transfected cells. Additionally, GIF-0890-r effectively inhibited the aggregate formation of human SOD1 G93A, a causative mutation of ALS. GIF-0827-r and GIF-0856-r also effectively inhibited aggregate formation of human prion protein (hPrP). Subsequently, the correlation between their inhibitory effects on cSOD1 and hPrP aggregation was shown, indicating GIF com-pounds inhibited the aggregate formation of multiple amyloidogenic proteins. Conclusively, the novel oxindole compounds (GIF-0827-r, GIF-0854-r, GIF-0856-r, and GIF-0890-r) are proposed as useful therapeutic candidates for amyloidogenic neurodegenerative disorders.