通过PROTAC介导的HDAC7蛋白降解揭示了其在巨细胞中的脱乙酶独立的抗炎功能
Kailibinuer Kadier1, Tian Niu1, Baoli Ding1
1Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|July 25, 2024
概括
研究人员开发了一种新型化合物来降解HDAC7,这是炎症的关键调节者. 这种有针对性的方法有效地减少了炎症性细胞因子,揭示了HDAC7.
科学领域:
- 表观遗传学和分子生物学
- 免疫学和炎症研究研究
- 药物发现和开发 药物发现和开发
背景情况:
- 第IIa类基因组脱乙酶 (HDACs) 是细胞代谢和炎症的关键调节剂.
- 目前的泛抑制性HDAC抑制剂限制了对单个HDAC异型函数的研究.
- 需要新的工具来研究超越表观遗传调节的HDAC功能.
研究的目的:
- 开发一种针对HDAC7降解的选择性化学探针.
- 研究HDAC7在炎症途径中的非表观遗传作用.
- 探索HDAC7作为抗炎治疗的治疗点.
主要方法:
- 开发一种用于选择性 HDAC7 降解的新型蛋白质分解向奇美拉 (PROTAC) 化合物 (B4).
- 在脂聚糖 (LPS) 刺激的巨细胞和小鼠模型中评估B4的疗效.
- 涉及托尔类受体4 (TLR4) 信号通路和蛋白质与蛋白质相互作用的机制研究.
主要成果:
- 化合物B4选择性降解了HDAC7,导致减少了促炎性细胞因子的产生.
- 发现HDAC7在炎症中的作用超出了它的脱乙酶活性.
- HDAC7被确定为TLR4-TRAF6-TAK1复合物的关键组成部分,激活MAPK/NF-κB信号传递.
结论:
- 选择性降解HDAC7提供了一个有前途的抗炎策略.
- 在炎症信号传递中,HDAC7的作用超出了它的表观遗传功能.
- 准HDAC7为炎症性疾病提供了一个新的治疗途径.
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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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