Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 143, Issue -, Pages 1578-1589Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.052
Keywords
Nrf2; Keap1; Protein-protein interaction inhibitors; Cyclic peptide
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Funding
- National Natural Science Foundation of China [81602948, 81230078, 81773639, 81773581]
- Natural Science Foundation of Jiangsu Province of China [BK20160746]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2015ZX09101032, 2017ZX09302003, 2017ZX09101004-003-006]
- Fundamental Research Funds for the Central Universities [2016ZPY016]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZCX201611]
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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 Keapi 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 Keapl 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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