Abstract
Host cdc2-like kinase 1 (CLK1) is responsible for the alternative splicing of the influenza virus M2 gene during influenza virus infection and replication that has been recognized as a potential anti-influenza virus target. In this study, we showed that gallocatechin-7-gallate (J10688), a novel CLK1 inhibitor isolated from Pithecellobium clypearia Benth, exerted potent anti-influenza virus activity in vivo and in vitro. ICR mice were intranasally infected with a lethal dose of H1N1. Administration of J10688 (30 mg·kg−1·d−1, iv, for 5 days) significantly increased the survival rate of the H1N1-infected mice to 91.67% and prolong their mean survival time from 5.83 ± 1.74 days to 13.66 ± 1.15 days. J10688 administration also slowed down body weight loss, significantly alleviated influenza-induced acute lung injury, reduced lung virus titer, elevated the spleen and thymus indexes, and enhanced the immunological function. We further explored its anti-influenza mechanisms in the H1N1-infected A549 cells: as a novel CLK1 inhibitor, J10688 (3, 10, 30 μmol/L) dose-dependently impaired synthesis of the viral proteins NP and M2, and significantly downregulated the phosphorylation of splicing factors SF2/ASF and SC35, which regulate virus M2 gene alternative splicing. As a novel CLK1 inhibitor with potent anti-influenza activity in vitro and in vivo, J10688 could be a promising antiviral drug for the therapy of influenza A virus infection.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81673480), the Beijing Natural Science Foundation (7152103), the CAMS Initiative for Innovative Medicine (CAMS-I2M; 2016-I2M-3-007), the National Great Science and Technology Projects (2012ZX09301002-2013HXW-11, 2014ZX09507003-002), and the International Collaboration Project (2011DFR31240).
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The contributions of the respective authors are as follows: A-lL and G-hD designed the research; CL, W-wL, L-jX, X-cP, and HJ performed the research; and CL wrote the paper. All authors read and approved the final manuscript.
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Li, C., Xu, Lj., Lian, Ww. et al. Anti-influenza effect and action mechanisms of the chemical constituent gallocatechin-7-gallate from Pithecellobium clypearia Benth. Acta Pharmacol Sin 39, 1913–1922 (2018). https://doi.org/10.1038/s41401-018-0030-x
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DOI: https://doi.org/10.1038/s41401-018-0030-x
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