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

Journal of Enzyme Inhibition and Medicinal Chemistry

Ricardo Bentes Azevedo¹  João Paulo Figueiró Longo¹  Juan Zhang²  Luis Alexandre Muehlmann²  Ning Meng³  Cheng-Shi Jiang³  Hua Zhang³  Kongkai Zhu³  Wen Zhang⁴  Chun-Lin Zhuang⁴ 

[1] Faculty of Ceilandia, University of Brasília, Brasilia, Brazil;Faculty of Ceilandia, University of Brasília, Brasilia, Brazil;Institute of Biological Sciences, University of Brasília, Brasilia, Brazi;School of Biological Science and Technology, University of Jinan, Jinan, China;School of Pharmacy, Second Military Medical University, Shanghai, China;

关键词: Keap1;    Nrf2;    protein–protein interaction inhibitor;    cytoprotective;    septic cardiomyopathy;   

DOI  :  10.1080/14756366.2018.1461856

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY