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

• Published in: Antiviral research 2011-09, Vol.91 (3), p.304-313
• Main Authors: Haasbach, Emanuel, Pauli, Eva-Katharina, Spranger, Robert, Mitzner, David, Schubert, Ulrich, Kircheis, Ralf, Planz, Oliver
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - therapeutic use; Biological and medical sciences; Cell Line, Tumor; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Drug Resistance, Viral; Drug-resistance; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - therapeutic use; Host-Pathogen Interactions; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - growth & development; Influenza A Virus, H5N1 Subtype - drug effects; Influenza A Virus, H5N1 Subtype - growth & development; Influenza, Human - drug therapy; Influenza, Human - virology; Lipopolysaccharides - adverse effects; Lipopolysaccharides - pharmacology; Lung - cytology; Lung - drug effects; Medical sciences; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - virology; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitor; Proteasome Inhibitors; Survival Rate; Virus Replication - drug effects
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2011.07.006

► Inhibition of the proteasome with VL-01 leads to reduced virus titer in vitro and in vivo. ► Proteasome inhibition shows a reduction of cytokines/chemokines after LPS or H5N1 infection. ► Aerosol treatment with VL-01 shows no toxic side effects in mice. 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 1.7 μM), A/Regensburg/D6/09 (H1N1v) (EC 50 value of 2.4 μM) and A/Mallard/Bavaria/1/2006 (H5N1) (EC 50 value of 0.8 μM). In in vivo experiments we could demonstrate that VL-01-aerosol-treatment of BALB/c mice with 14.1 mg/kg results in no toxic side effects, reduced progeny virus titers in the lung (1.1 ± 0.3 log 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-α/β, IL-6, MIP-1β, RANTES and TNF-α 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.