Cyclic Peptide Keap1–Nrf2 Protein–Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury
Jihua Zou, Jianyu Yan, Yifei Lü, Yu Zhou, Kai Zhang, Qianyu Han, Dan Han, Conghao Gai, Xiaoyun Chai, Qingjie Zhao, Chunlin Zhuang, Yan Zou
Abstract
Directly blocking the Keap1–Nrf2 pathway is a promising strategy for the mitigation of acute lung injury (ALI). Peptide Keap1–Nrf2 inhibitors have been reported to have a high Keap1 binding affinity. However, these inhibitors showed weak activity in cells and/or animals. In this study, we designed a series of linear peptides from an Nrf2-based 9-mer Ac-LDEETGEFL-NH 2 . To improve the cellular activity, we further designed cyclic peptides based on the crystal complex of Keap1 with a linear peptide. Among them, cyclic 9-mer ZC9 targeting Keap1 showed a better affinity ( K D2 = 51 nM). Specifically, it exhibited an acceptable water solubility (>38 mg/mL), better cell permeability, cell activity, and metabolic stability (serum t 1/2 > 24 h). In the in vitro LPS-induced oxidative damages and ALI model, ZC9 showed significant dose–response reversal activity without apparent toxicity. In conclusion, our results suggested ZC9 as a lead cyclic peptide targeting the Keap1–Nrf2 pathway for ALI clinical treatment.