一种细胞活性循环,向Nrf2/Keap1蛋白与蛋白相互作用
Jessica Iegre1, Sona Krajcovicova1,2, Anders Gunnarsson3
1Yusuf Hamied Department of Chemistry Lensfield Road CB2 1EW Cambridge UK spring@ch.cam.ac.uk.
Chemical science
|October 13, 2023
概括
研究人员开发了一种新的接策略,以抑制Nrf2/Keap1蛋白-蛋白相互作用,这对于治疗氧化应激疾病至关重要. 一个被脂肪酸标记的酸实现了纳米分子亲和力和细胞活性,提供了一个有前途的治疗途径.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- Nrf2/Keap1蛋白与蛋白相互作用 (PPI) 是各种疾病中抗氧化应激的关键目标.
- 类提供了一个潜在的治疗策略来抑制这种PPI,补充小分子.
研究的目的:
- 开发一种用于向Nrf2/Keap1 PPI的新型基分离策略.
- 创建受约束和功能化的,以提高活性和细胞功效.
主要方法:
- 采用了双组分接方法.
- 被功能化,包括脂肪酸标签 (P8-H).
- 评估了结合亲和力,细胞活性 (ARE基因转录) 和结构分析 (晶体学).
主要成果:
- 该P8-H表明了对Keap1.1.的纳米分子亲和力.
- 它在微小分子度下有效地诱导了人类肺上皮细胞系的ARE基因转录.
- 获得了基AP1复合体的高分辨率晶体结构.
结论:
- 接策略成功产生了强大的Nrf2/Keap1 PPI 抑制剂.
- 酸P8-H代表了一种有前途的化合物用于治疗开发.
- 获得的晶体结构有助于设计细胞透性胺抑制剂.
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