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

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·d, 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.

Flavonoids as Promising Antiviral Agents against SARS-CoV-2 Infection: A Mechanistic Review

“…Additionally, assessments on H1N1-infected A549 cells demonstrated a significant downregulation of viral NP and M2 mRNAs. Moreover, the phosphorylation of splicing factors SF2/ASF and SC35, key factors for virus M2 gene alternative splicing, was significantly decreased after treatment with gallocatechin-7-gallate [ 58 ]. Cirsimaritin (CST), a flavonoid from Artemisia scoparia Waldst.…”

“…In addition to the above, gallocatechin-7-gallate, genistein and theaflavins are other flavonoids with modulating effects on the production of pro-inflammatory cytokines [ 58 , 76 , 108 ]; thus, these molecules seem to have a desirable anti-inflammatory effect, helpful in controlling viral infection-related inflammation.…”

Network-Based Identification and Experimental Validation of Drug Candidates Toward SARS-CoV-2 via Targeting Virus–Host Interactome

“…As a novel host cdc2-like kinase 1 inhibitor, gallocatechin-7-gallate which was isolated from P . clypearia ( Li et al, 2016 ) exhibited potent in vivo and in vitro activities against influenza virus ( Li et al, 2018 ). For instance, gallocatechin-7-gallate could significantly improve the survival rate of the mice that were infected with H1N1 virus and reduce the lung virus titer, indicating a promising drug candidate for antiviral therapy ( Li et al, 2018 ).…”

Substantial effect of phytochemical constituents against the pandemic disease influenza—a review

“…Increase survival rate by prevent viral infection and lung injury iv. Decrease viral NP, M2, and RNA synthesis Influenza A H1N1, H3N2 and B A/PR/8/34 (H1N1), A/Sydney/5/97 (H3N2), and B/Jiangsu/10/2003 [ 120 ] 32 Pogostemon cablin Lamiaceae Dried aerial part Sesquiterpene: Patchouli alcohol i. Target virus particles and cellular PI3K/Akt and ERK/MAPK signaling pathways ii.…”

“…Alternative splicing of the influenza virus M2 gene depends on the host cdc2-like kinase 1 (CLK1). J10688 was an effective CLK1 inhibitor, by downregulating SC35 and SF2/ASF excessive phosphorylation and thereby controlling M2 mRNA alternative splicing [ 120 ].…”