Identification of a Novel Small-molecule Keap1-Nrf2 PPI Inhibitor with Cytoprotective Effects on LPS-induced Cardiomyopathy

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2018 Apr 26

PMID 29693453

Citations 25

Authors

Cheng-Shi Jiang

Chun-Lin Zhuang

Kongkai Zhu

Juan Zhang

Luis Alexandre Muehlmann

Joao Paulo Figueiro Longo

Ricardo Bentes Azevedo

Wen Zhang

Ning Meng

Hua Zhang

Affiliations

Soon will be listed here.

Abstract

A new Keap1-Nrf2 protein-protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 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 in vivo mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, ZJ01 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 ZJ01 is a promising drug lead for septic cardiomyopathy treatment. ZJ01 was identified as a new Keap1-Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by in vitro and in vivo experiments.

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