Antiviral activity of the proteasome inhibitor VL-01 against influenza A viruses.

摘要

The appearance of highly pathogenic avian influenza A viruses of the H5N1 subtype being able to infect humans and the 2009 H1N1 pandemic reveals the urgent need for new and efficient countermeasures against these viruses. The long-term efficacy of current antivirals is often limited, because of the emergence of drug-resistant virus mutants. A growing understanding of the virus-host interaction raises the possibility to explore alternative targets involved in the viral replication. In the present study we show that the proteasome inhibitor VL-01 leads to reduction of influenza virus replication in human lung adenocarcinoma epithelial cells (A549) as demonstrated with three different influenza virus strains, A/Puerto Rico/8/34 (H1N1) (EC(50) value of 1.7muM), A/Regensburg/D6/09 (H1N1v) (EC(50) value of 2.4muM) and A/Mallard/Bavaria/1/2006 (H5N1) (EC(50) value of 0.8muM). In in vivo experiments we could demonstrate that VL-01-aerosol-treatment of BALB/c mice with 14.1mg/kg results in no toxic side effects, reduced progeny virus titers in the lung (1.1+/-0.3log(10)pfu) and enhanced survival of mice after infection with a 5-fold MLD(50) of the human influenza A virus strain A/Puerto Rico/8/34 (H1N1) up to 50%. Furthermore, treatment of mice with VL-01 reduced the cytokine release of IL-alpha/beta, IL-6, MIP-1beta, RANTES and TNF-alpha induced by LPS or highly pathogen avian H5N1 influenza A virus. The present data demonstrates an antiviral effect of VL-01 in vitro and in vivo and the ability to reduce influenza virus induced cytokines and chemokines.