Abstract
Influenza A virus (IAV) poses a severe threat to human health and is a major public health problem worldwide. As global anti-influenza virus drug resistance has increased significantly, there is an urgent need to develop new antiviral drugs, especially drugs from natural products. Isoimperatorin, an active natural furanocoumarin, exhibits a broad range of pharmacologic activities including anticoagulant, analgesic, anti-inflammatory, antibacterial, anti-tumor, and other pharmacological effects, so it has attracted more and more attention. In this study, the antiviral and mechanistic effects of isoimperatorin on influenza A virus in vitro were studied. Isoimperatorin illustrated a broad-spectrum antiviral effect, especially against the A/FM/1/47 (H1N1), A/WSN/33 (H1N1, S31N, amantadine resistant), A/Puerto Rico/8/34 (H1N1), and A/Chicken/Guangdong/1996 (H9N2) virus strains. The experimental results of different administration modes showed that isoimperatorin had the best antiviral activity under the treatment mode. Further time-of-addition experiment results indicated that when isoimperatorin was added at the later stage of the virus replication cycle (6–8 h, 8–10 h), it exhibited an effective antiviral effect, and the virus yield was reduced by 81.4 and 84.6%, respectively. In addition, isoimperatorin had no effect on the expression of the three viral RNAs (mRNA, vRNA, and cRNA). Both the neuraminidase (NA) inhibition assay and CETSA demonstrated that isoimperatorin exerts an inhibitory effect on NA-mediated progeny virus release. The molecular docking experiment simulated the direct interaction between isoimperatorin and NA protein amino acid residues. In summary, isoimperatorin can be used as a potential agent for the prevention and treatment of influenza A virus.
Highlights
Influenza virus, a single-stranded negative-strand RNA virus of Orthomyxoviridae, is an important respiratory pathogen that has a significant impact on global health
The Cytopathic Effect (CPE) reduction assay showed that isoimperatorin could distinctly protect Madin-Darby canine kidney (MDCK) cells from influenza virus-induced cell cytopathic effects (CPEs) (Figure 2D), with an EC50 value of 0.73 μM and selectivity index (SI) value > 274.65 (Table 1)
Plaque reduction assays were used to evaluate the effect of isoimperatorin on the titre of progeny virus in the cell supernatant, and the results were consistent with the expression of viral nucleoprotein (Figure 3B)
Summary
A single-stranded negative-strand RNA virus of Orthomyxoviridae, is an important respiratory pathogen that has a significant impact on global health. Due to the high mutation rate of virus genes, effective virus transmission, rapid emergence of drug resistance and the limited effectiveness of currently available therapies, the spread of the virus can cause a pandemic. Since the global influenza pandemic in 1918, the outbreak caused by the influenza virus, this virus has caused 50 million deaths in this century (Jester et al, 2019). Influenza A viruses are divided into many subtypes according to H and N antigens. H1N1, H2N2, and H3N2 mainly infect humans. There are three types of effective anti-influenza drugs approved by the FDA
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