Abstract
Infections with influenza A viruses (IAV) are still amongst the major causes of highly contagious severe respiratory diseases not only bearing a devastating effect to human health, but also significantly impact the economy. Besides vaccination that represents the best option to protect from IAV infections, only two classes of anti-influenza drugs, inhibitors of the M2 ion channel and the neuraminidase, often causing resistant IAV variants have been approved. That is why the need for effective and amply available antivirals against IAV is of high priority. Here we introduce LADANIA067 from the leaves of the wild black currant (Ribes nigrum folium) as a potent compound against IAV infections in vitro and in vivo. LADANIA067 treatment resulted in a reduction of progeny virus titers in cell cultures infected with prototype avian and human influenza virus strains of different subtypes. At the effective dose of 100 µg/ml the extract did not exhibit apparent harming effects on cell viability, metabolism or proliferation. Further, viruses showed no tendency to develop resistance to LADANIA067 when compared to amantadine that resulted in the generation of resistant variants after only a few passages. On a molecular basis the protective effect of LADANIA067 appears to be mainly due to interference with virus internalisation. In the mouse infection model LADANIA067 treatment reduces progeny virus titers in the lung upon intranasal application. In conclusion, an extract from the leaves of the wild black currant might be a promising source for the development of new antiviral compounds to fight IAV infections.
Highlights
Influenza A viruses (IAV), family members of the genera Orthomyxoviridae, are characterised by a negative oriented, segmented single strand RNA genome
In a first set of experiments we investigated whether LADANIA067 exerts an antiviral effect against influenza A virus (IAV) infection in cultured cells
A549 cells were treated with LADANIA067 for different time periods and were stained with propidium-iodide (PI) to monitor cell death (Fig. 2D)
Summary
Influenza A viruses (IAV), family members of the genera Orthomyxoviridae, are characterised by a negative oriented, segmented single strand RNA genome. The continuous and rapid emergency of new highly pathogenic avian influenza virus (HPAIV) of the H5N1 type, transmitting from poultry to human, and the recent pandemic H1N1v IAV outbreak, to which no vaccines had been amply available in time, highlight the urgent need of effective antivirals to fight influenza viruses. Two classes of antivirals that either target the M2 protein (amantadine, rimantadine) or the neuraminidase (NA) (oseltamivir, zanamivir) of IAV are available. These compounds are characterised by rapid resistance development. Due to the obvious need for new and amply available antiviral agents that do not show any tendency to cause toxic side effects or generate resistant virus variants, the use of plant-derived extracts or compounds received increasing attention. Various studies have demonstrated the antiviral potential of plant-derived compounds in cell culture, studies that explore their molecular mode of action or their activity in vivo are still scarce
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