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.
Highlights
Sepsis, a major cause of death worldwide, is a systemic inflammatory syndrome caused by serious infections[1]
We describe the identification of ZJ01 as a new Kelch-like ECH-associated protein 1 (Keap1)–Nrf[2] PPI inhibitor and further investigate its in vitro and in vivo cytoprotective effects on LPS-induced cardiomyopathy
Condensation of (1,3-benzothiazol-2-yl)acetonitrile (1) with 4-(diethylamino)2-hydroxybenzaldehyde (2) readily produced the intermediate 323, which was converted to the target compounds by reaction with allyl carbonochloridate or acryloyl chloride
Summary
A major cause of death worldwide, is a systemic inflammatory syndrome caused by serious infections[1]. Up to 70% of patients with sepsis are affected by septic cardiomyopathy, and the dysfunction of cardiomyocytes contributes to a high mortality rate[2]. Lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria, has proven to be a key stimulator of sepsis[3]. LPS can evoke an inflammatory response in innate immune cells, as well as non-immune cells (e.g. cardiomyocytes) expressing LPS-pattern recognition receptors[4]. Cardiac dysfunction frequently occurs in patients with sepsis and animals injected with LPS5,6. Increasing evidence indicates that control of the oxidative stress and inflammatory response in cardiomyocytes could alleviate LPS-induced cardiac injury[7,8,9]
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