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In light of the recent novel H1N1 virus epidemic, virus resistance to currently approved antiviral medications has become a global health concern. Since almost all circulating strains of influenza A viruses are resistant to either adamantanes or neuraminidase inhibitors, new therapeutic approaches and means to discover new antiviral agents are critical to address the issue of recurring drug resistance. We postulate that computational molecular docking provides an efficient and innovative approach to examine small molecules against influenza viruses. We have identified a potent inhibitor of the H5N1 neuraminidase protein from a library of 23,000 compounds. This compound demonstrated anti-viral activity efficacy in vitro across a number of cell-lines assays in H5N1, H1N1, H9N2/G1, H3N2 and the oseltamivir-resistant H1N1 virus while the compound itself did not show any cytotoxicity. The underlying mechanisms including immunoregulation, upstream signalling pathways and neuraminidase inhibitory activity were also studied. It was found that the compound inhibit the viral titers via inhibiting the neuraminidase activity. Upon successful demonstration of the effectiveness of the compound in the cell culture model, we further validated the anti-influenza effect of the compound in a mouse model. BALB/c mice were administrated once daily with the compound or diluent control (DMSO). They were then intranasally infected with A/PR/8/34 influenza virus. The mice were treated with the compound or DMSO through oral gavage for five more days starting from 8 h post-infection. Our results showed that the compound prolonged the life span and increased the survival rate of the mice. These results demonstrated that the compound screened from molecular docking is a new potential drug candidate for inhibiting viral replications of different influenza viruses. |
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