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

作　　者：Chao Li Lv-jie Xu Wen-wen Lian Xiao-cong Pang Hao Jia Ai-lin Liu Guan-hua Du 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2018年第12期1913-1922,共10页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China {81673480);the Beijing Natural Science Foundation (7152103);the CAMS Initiative for Innovative Medicine (CAMS-12M;2016-12M-3-007);the National Great Science and Technology Projects (2012ZX09301002-2013HXW-11,2014ZX09507003-002); the International Collaboration Project (2011DFR31240).

摘　　要：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 (30mg·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, 30μmol/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.

关 键 词：INFLUENZA VIRUS cdc2-like KINASE 1 gallocatechin-7-gallate Pithecellobium clypearia Benth traditional Chinese medicine 

分 类 号：R[医药卫生]