Identification of a novel small-molecule Keap1-Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy.
Identification of a novel small-molecule Keap1-Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy.
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鉴定一种新型小分子 Keap1-Nrf2 PPI 抑制剂，对 LPS 诱导的心肌病具有细胞保护作用
DOI：
10.1080/14756366.2018.1461856
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发表时间：
2018-12
影响因子：
5.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Jiang CS;Zhuang CL;Zhu K;Zhang J;Muehlmann LA;Figueiró Longo JP;Azevedo RB;Zhang W;Meng N;Zhang H
通过荧光偏振分析、表面等离子体共振、分子对接和分子动力学模拟，从我们的化合物文库中鉴定出一个新的Keap1-Nrf2蛋白相互作用(PPI)抑制剂ZJ01。ZJ01可在体外触发Nrf2核转位，导致Nrf2靶基因HO-1和NQO1的mRNA水平升高。同时，ZJ01抑制脂多糖诱导的H9c2心肌细胞ROS的产生及促炎细胞因子Tf-α、IL-1β和IL-6m RNA的表达。此外，在腹腔注射脂多糖诱导的败血症心肌病小鼠体内模型中，ZJ01具有细胞保护作用，上调Nrf2蛋白的核积聚，并显著抑制上述细胞因子水平。这些结果为开发直接的Keap1-Nrf2 PPI抑制剂提供了一种新的化学类型，并提示化合物ZJ01是治疗感染性心肌病的有前途的药物先导。通过体外和体内实验，确定ZJ01是一种新的Keap1-Nrf2 PPI抑制剂和治疗感染性心肌病的药物先导。
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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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
3.7
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Hao E;Lang F;Chen Y;Zhang H;Cong X;Shen X;Su G
通讯作者：
Su G
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML