Jiang Zheng-Yu, Lu Meng-Chen, You Qi-Dong
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
J Med Chem. 2016 Dec 22;59(24):10837-10858. doi: 10.1021/acs.jmedchem.6b00586. Epub 2016 Oct 12.
The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors.
转录因子Nrf2是细胞防御系统的主要调节因子，增强Nrf2活性在各种疾病，特别是与年龄相关的慢性疾病和炎症性疾病中具有潜在用途。最近，直接靶向Keap1-Nrf2蛋白-蛋白相互作用（PPI）已成为一种选择性和有效激活Nrf2的新兴策略。本综述总结了Keap1-Nrf2 PPI抑制剂发现与开发的进展，包括Keap1-Nrf2调控机制、抑制剂鉴定的生化技术、肽和小分子抑制剂的鉴定方法，并讨论了Keap1-Nrf2 PPI抑制剂的优势结构和进一步开发的未来方向。
