title: Antiviral activity of the proteasome inhibitor VL-01 against influenza A viruses.
abstract: 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) (EC50 value of 1.7 μM), A/Regensburg/D6/09 (H1N1v) (EC50 value of 2.4 μM) and A/Mallard/Bavaria/1/2006 (H5N1) (EC50 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 log10 pfu) and enhanced survival of mice after infection with a 5-fold MLD50 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.
authors.affiliation: Friedrich-Loeffler-Institut, Institute of Immunology, Paul-Ehrlich Str. 28, 72076 Tuebingen, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Haasbach
authors.forename: Eva-Katharina
authors.initials: EK
authors.lastname: Pauli
authors.forename: Robert
authors.initials: R
authors.lastname: Spranger
authors.forename: David
authors.initials: D
authors.lastname: Mitzner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schubert
authors.forename: Ralf
authors.initials: R
authors.lastname: Kircheis
authors.forename: Oliver
authors.initials: O
authors.lastname: Planz
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000254:growth & development; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000254:growth & development; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015996:Survival Rate; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex