Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

Abstract

<p>A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor <b>ZJ01</b> was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. <b>ZJ01</b> could <i>in vitro</i> trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, <b>ZJ01</b> suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells. Moreover, in an <i>in vivo</i> mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, <b>ZJ01</b> demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound <b>ZJ01</b> is a promising drug lead for septic cardiomyopathy treatment.</p> <p><b>ZJ01</b> was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by <i>in vitro</i> and <i>in vivo</i> experiments.</p