Emerging Substrate Proteins of Kelch-like ECH Associated Protein 1 (Keap1) and Potential Challenges for the Development of Small-Molecule Inhibitors of the Keap1-Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Protein-Protein Interaction.
Emerging Substrate Proteins of Kelch-like ECH Associated Protein 1 (Keap1) and Potential Challenges for the Development of Small-Molecule Inhibitors of the Keap1-Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Protein-Protein Interaction.
复制标题
Kelch 样 ECH 相关蛋白 1 (Keap1) 的新兴底物蛋白以及 Keap1-核因子红细胞 2 相关因子 2 (Nrf2) 蛋白-蛋白相互作用小分子抑制剂开发的潜在挑战。
DOI：
10.1021/acs.jmedchem.9b01865
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发表时间：
2020
影响因子：
7.3
通讯作者：
Peng Ying
中科院分区：
文献类型：
--
作者：
Zhong Yong;Shi Zeyu;Zhou Yujun;Xiao Qiong;Wang Hongyue;Peng Ying
核因子红细胞2相关因子2 （Nrf2）的激活被认为是对抗氧化应激和炎症的一种有希望的治疗慢性疾病的策略。最近，直接抑制Nrf2与kelch样ECH相关蛋白1 （Keap1）之间的蛋白相互作用（PPI）已成为生物体中激活Nrf2的一种有吸引力的策略。目前Keap1-Nrf2 PPI抑制剂的开发主要基于Keap1与Nrf2 ETGE基序的相互作用。然而，在过去的十年中，一组具有与Nrf2相似的ETGE基序的蛋白质已经成为Keap1的新底物。从这个角度来看，我们将重点关注当前Keap1-Nrf2 PPI抑制剂的潜在脱靶作用，并讨论它们对未来药物开发的影响。我们还提出了一种基于DLGex的策略，旨在抑制Keap1-Nrf2 DLGex相互作用，这将有助于开发具有更好靶向选择性的小分子。
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to combat both oxidative stress and inflammation as a promising strategy to treat chronic diseases. Recently, directly inhibiting the protein–protein interaction (PPI) between Nrf2 and Kelch-like ECH associated protein 1 (Keap1) has emerged as an attractive strategy to activate Nrf2 in organisms. The current development of Keap1-Nrf2 PPI inhibitors is mainly based on the interaction between Keap1 and the Nrf2 ETGE motif. However, a group of proteins that feature an ETGE motif similar to that of Nrf2 have emerged as new substrates of Keap1 over the past decade. In this Perspective, we focus on the potential off-target actions of current Keap1-Nrf2 PPI inhibitors and discuss their impact on future drug development. We also propose that a DLGex-based strategy aiming to inhibit the Keap1-Nrf2 DLGex interaction would help the development of small molecules with better target selectivity.