Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 33, Issue 1, Pages 833-841Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2018.1461856
Keywords
Keap1; Nrf2; protein-protein interaction inhibitor; cytoprotective; septic cardiomyopathy
Funding
- National Natural Science Foundation of China [21672082, 31671214]
- Shandong Key Development Project [2016GSF201209]
- Young Taishan Scholars Program [tsqn20161037]
- Shandong Talents Team Cultivation Plan of University Preponderant Discipline [10027]
- Shandong Province Natural Science Foundation [ZR2017BH038]
- University of Jinan [XKY1609, 160100202]
- Shanghai ChenGuang Project [16CG42]
- Shanghai Municipal Commission of Health and Family Planning [2017YQ052]
- FAP/DF [0193.001020/2015]
- CNPq [447.628/2014-3]
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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-alpha, IL-1 beta 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. [GRAPHICS] .
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