Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones.
Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones.
复制标题
鉴定作为化学伴侣抑制内质网应激诱导的细胞死亡的新型羟吲哚化合物。
DOI：
10.1021/acschemneuro.2c00064
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hirata Y
中科院分区：
文献类型：
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作者：
Hasegawa Y;Motoyama M;Hamamoto A;Kimura S;Kamatari YO;Kamishina H;Oh-Hashi K;Furuta K;Hirata Y
内质网（ER）应激和氧化应激导致蛋白质错误折叠，并且所导致的蛋白质聚集体的积累通常与神经退行性疾病的发病机制相关，包括阿尔茨海默病、帕金森病、肌萎缩性侧索硬化和朊病毒病。预防这些致病过程的小分子可能是这种神经退行性疾病的有效干预措施。在本文中，我们确定了几种新的羟吲哚化合物，可以防止ER应激和氧化应激诱导的细胞死亡。其中，先导化合物GIF-0726-r的衍生物（其中羟吲哚环5位的氢原子被甲基（GIF-0852-r）、溴（GIF-0854-r）或硝基（GIF-0856-r）基团取代）有效地抑制了整体ER应激。此外，GIF-0854-r和-0856-r在体外和培养的海马HT 22神经元细胞中阻止蛋白聚集体的积累，表明这两种化合物有效地发挥化学伴侣的功能。此外，GIF-0852-r、GIF-0854-r和GIF-0856-r可预防谷氨酸诱导的氧化和erastin诱导的铁凋亡。总之，这些结果表明，新的羟吲哚化合物GIF-0854-r和-0856-r可能是有用的治疗剂对蛋白质错误折叠疾病，以及有价值的研究工具，研究ER和氧化应激的分子机制。
Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress- and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulationin vitroand in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamate-induced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.