Article

Anti-influenza effect and action mechanisms of the chemical constituent gallocatechin-7-gallate from Pithecellobium clypearia Benth

Authors: Chao Li1,2, Lv-jie Xu1, Wen-wen Lian1, Xiao-cong Pang1, Hao Jia1, Ai-lin Liu1,3,4, Guan-hua Du1,3,4
1 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2 Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
3 Beijing Key Laboratory of Drug Target Research and Drug Screening, Beijing 100050, China
4 State Key Laboratory of Natural Active Substances and Functions, Beijing 100050, China
Correspondence to: Ai-lin Liu: liuailin@imm.ac.cn, Guan-hua Du: dugh@imm.ac.cn,
DOI: 10.1038/s41401-018-0030-x
Received: 14 December 2017
Accepted: 17 April 2018
Advance online: 25 May 2018

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·kg1·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.
Keywords: influenza virus; cdc2-like kinase 1; gallocatechin-7-gallate; Pithecellobium clypearia Benth; traditional Chinese medicine

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