Cyclic Peptide Keap1–Nrf2 Protein–Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury

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-NH2. 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 (KD2 = 51 nM). Specifically, it exhibited an acceptable water
solubility (>38 mg/mL), better cell permeability, cell activity,
and
metabolic stability (serum t1/2 > 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.