Keap1-Nrf2蛋白相互作用小分子抑制剂及降解剂研究进展

Advances on Keap1-Nrf2 protein-protein interaction inhibitors and degraders

氧化应激是机体内一种氧化还原失衡状态,是导致组织损伤和疾病发生的重要因素之一。核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)-Kelch样环氧氯丙烷相关蛋白1(Kelch like ECH-associated protein 1,Keap1)信号通路不仅是抵御氧化应激损伤的重要防御系统,也是增强机体抗氧化能力的关键信号通路之一。大量研究表明,靶向Keap1-Nrf2信号通路并激活Nrf2已经成为治疗氧化应激和相关疾病的有效策略。运用小分子直接阻断Keap1-Nrf2蛋白-蛋白相互作用(protein-protein interaction,PPI)是激活Nrf2并且发挥保护作用的重要方向之一,可以避免共价修饰激活Nrf2的潜在不良反应。另一方面,Keap1作为新型E3泛素化酶工具,已被用于蛋白水解靶向嵌合体(proteolysis targeting chimeras,PROTACs)的设计。本文综述了近年来Keap1-Nrf2蛋白相互作用抑制剂和基于Keap1 E3泛素化系统的降解剂的研究进展。

Oxidative stress is a redox imbalance in the body,which is one of the important factors leading to tissue damage and diseases.The nuclear factor E2-related factor 2(Nrf2)-Kelch like ECH-associated protein 1(Keap1)signaling pathway is not only an important defense system against oxidative damage,but also one of the key signaling pathways of the antioxidant capacity.Numerous studies have shown that targeting the Keap1-Nrf2signaling pathway to activate Nrf2 has become an effective strategy for the treatment of oxidative stress and related diseases.Using small molecules to directly block the Keap1-Nrf2 protein-protein interaction(PPI)is one of the important directions for activating Nrf2 and exerting the cytoprotective effect,which can avoid the potential side effects of covalent modification of Nrf2.On the other hand,the Keap1 is an efficient E3 ubiquitin ligase that has been used in the design of proteolysis targeting chimeras(PROTACs).This review summarizes the research progresses of Keap1-Nrf2 protein interaction inhibitors and degraders based on the Keap1 E3 ubiquitination system in recent years.