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European journal of medicinal chemistry v.143, 2018년, pp.1578 - 1589   SCI SCIE
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Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency

Lu, Meng-Chen (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; Jiao, Qiong (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; Liu, Tian (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; Tan, Shi-Jie (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; Zhou, Hai-Shan (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; You, Qi-Dong (State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ) ; Jiang, Zheng-Yu (State Key Laboratory of Natural Medicines, Jiangsu Key Laborator ) ;
  • 초록  

    Abstract Directly disrupting Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a novel way to activate Nrf2. Peptide Keap1-Nrf2 PPI inhibitors have been reported with high Keap1 binding affinity. However, these peptide inhibitors show weak activity in cells. In this study, the head-to-tail cyclic strategy was applied in the development of peptide inhibitors. The privileged residue sequence with minimal acidic residues was used as the template for the cyclic peptide, and the appropriate conjugation method was designed based on the peptide-Keap1 binding mode. The glycine was introduced as the linker to connect both sides, which can avoid the terminal charge, enhance the peptide stability and constrain the binding conformation simultaneously. The obtained novel cyclic peptide 3 showed high binding affinity with Keap1 and possessed high potency in Nrf2 activation at cellular level. We also showed that peptide 3 exhibited effective anti-inflammatory effects in mouse RAW 264.7 cells by activating the Nrf2-regulated defense system and enhancing the antioxidant capacity. This study proved that the head-to-tail cyclic strategy is quite useful in improving the cell potency of peptide Keap1-Nrf2 inhibitors and provided a possible way to develop drug-like peptides as therapeutic Nrf2 activators. Highlights The head-to-tail cyclization strategy is applied in the development of cyclic peptide Keap1-Nrf2 inhibitors. The obtained novel cyclic peptide 3 shows high binding affinity and prolonged residence time with Keap1. The cyclic peptide 3 possesses superior cellular potency in Nrf2 activation and antioxidant capacity. The cyclic peptide 3 displays effective anti-inflammatory effects in mouse RAW 264.7 cells. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Nrf2 .   Keap1 .   Protein-protein interaction inhibitors .   Cyclic peptide.  

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