通过促进Keap1降解来发现NAFLD改善剂
Mingming Qi1, Hui Zhong1, Zhaoyan Cheng2
1State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Journal of medicinal chemistry
|June 30, 2023
概括
这项研究引入了PROTAC I-d,这是一种新型化合物,可以降解Keap1以激活Nrf2,有效治疗非酒精性脂肪肝 (NAFLD),与传统抑制剂相比,毒性降低.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 肝病学 肝病学是一种肝病学.
背景情况:
- 通过Keap1抑制激活Nrf2,可以对抗氧化应激和NAFLD等疾病.
- 传统的Keap1抑制剂具有非目标效应.
- PROTAC技术为有针对性的Keap1降解提供了一种新的方法.
研究的目的:
- 为潜在的NAFLD治疗设计和合成针对Keap1降解的PROTAC.
- 在NAFLD模型中评估PROTAC I-d的疗效和安全性.
主要方法:
- 使用CDDO作为Keap1连接体合成PROTACs.
- 在体外 (AML12细胞) 和体内 (MCD饮食小鼠) 评估Keap1降解和Nrf2激活.
- 肝硬化症,肝硬化性肝炎和纤维化抑制的评估.
主要成果:
- PROTAC I-d显示了最佳的Keap1降解和增加的Nrf2水平.
- 在细胞和动物模型中,PROTAC I-d有效地减轻了氧化应激.
- PROTAC I-d显著抑制了肝硬化,肝硬化和纤维化,毒性低于CDDO.
结论:
- PROTAC I-d是一种强大的Keap1降解剂,对NAFLD具有显著的治疗潜力.
- PROTAC技术为开发更安全,更有效的NAFLD治疗提供了一个有前途的战略.
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