Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors

Abstract

Direct interference with Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has recently been introduced as an attractive approach to control life-threatening diseases like myocarditis. The present study aimed to investigate the potential application in myocarditis of a series of novel non-naphthalene derivatives as potential Keap1-Nrf2 PPI inhibitors. Our results indicated that the optimal compound K22 displayed the highest metabolic stability and showed notable Keap1-Nrf2 PPI inhibitory activities in vitro. K22 effectively triggered Nrf2 activation and increased the protein and mRNA expression of Nrf2-regulated genes in H9c2 cells. Moreover, pre-treatment with K22 was shown to mitigate LPS-induced damage to H9c2 cells, causing a marked decrease in the levels of inflammatory factors as well as reactive oxygen species (ROS). Furthermore, K22 was also shown to be non-mutagenic in the Ames test. Overall, our findings suggest that K22 may be a promising drug lead as a Keap1-Nrf2 PPI inhibitor for myocarditis treatment.

Graphical Abstract

Keywords:

• Keap1-Nrf2 PPI inhibitor
• drug design
• synthesis
• inflammatory response
• oxidative stress
• myocarditis

Authors’ contributions

Y.Y. and S.S initiated and supervised the research. Y.S, L.Z, and B.Y designed and performed the research. S.G, Q.L, and M.Z, contributed parts of the research. Y.S, L.Z, and B.Y wrote the manuscript, and all authors read and revised the final manuscript.

Additional information

Funding

This research was supported by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQY20H300001 and No. LYY19H310006.