A Plant Extract of Ribes nigrum folium Possesses Anti-Influenza Virus Activity In Vitro and In Vivo by Preventing Virus Entry to Host Cells

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

Pharmacodynamics, Pharmacokinetics, and Antiviral Activity of BAY 81-8781, a Novel NF-κB Inhibiting Anti-influenza Drug

Influenza is a respiratory disease that causes annual epidemics. Antiviral treatment options targeting the virus exist, but their efficiency is limited and influenza virus strains easily develop resistance. Thus, new treatment strategies are urgently needed. In the present study, we investigated the anti-influenza virus properties of D,L-lysine acetylsalicylate ⋅ glycine (BAY 81-8781; LASAG) that is approved as Aspirin i.v. for intravenous application. Instead of targeting the virus directly BAY 81-8781 inhibits the activation of the NF-κB pathway, which is required for efficient influenza virus propagation. Using highly pathogenic avian influenza virus strains we could demonstrate that BAY 81-8781 was able to control influenza virus infection in vitro. In the mouse infection model, inhalation of BAY 81-8781 resulted in reduced lung virus titers and protection of mice from lethal infection. Pharmacological studies demonstrated that the oral route of administration was not suitable to reach the sufficient concentrations of BAY 81-8781 for a successful antiviral effect in the lung. BAY 81-8781 treatment of mice infected with influenza virus started as late as 48 h after infection was still effective in protecting 50% of the animals from death. In summary, the data represent a successful proof of the novel innovative antiviral concept of targeting a host cell signaling pathway that is required for viral propagation instead of viral structures