title: The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo.
abstract: Influenza viruses (IV) continue to pose an imminent threat to human welfare. Yearly re-occurring seasonal epidemic outbreaks and pandemics with high mortality can occur. Besides vaccination against a limited number of viral strains only a few antiviral drugs are available, which are losing their effectiveness as more and more IV strains become resistant. Thus, new antiviral approaches that omit IV resistance are urgently needed. Here, the dependency on the cellular Raf/MEK/ERK signaling pathway for IV replication opens a new perspective. In consequence, we studied the antiviral potential of the MEK inhibitor Cl-1040 (PD184352). We show that Cl-1040 significantly reduces virus titers in vitro via retention of viral RNP complexes in the cell nucleus. Furthermore, Cl-1040 is effective against a broad range of IV strains, including highly pathogenic avian IV, as well as against a Tamiflu®-resistant IV strain. Using a mouse model, we demonstrate that Cl-1040 can reduce IV lung titers in vivo. Importantly, the treatment window for Cl-1040 expands up to 48 h post infection when Tamiflu®treatment has no effect. In conclusion, Cl-1040 offers an interesting perspective for anti-IV approaches.
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University Tuebingen, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Haasbach
authors.affiliation: Institute for Medical Virology, Justus Liebig University, Giessen, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Müller
authors.affiliation: Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University Muenster, Germany; Interdisciplinary Center of Clinical Research (IZKF), Medical Faculty, Westfaelische Wilhelms-University Muenster, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ehrhardt
authors.affiliation: Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University Muenster, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: Institute for Medical Virology, Justus Liebig University, Giessen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.affiliation: Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University Muenster, Germany; Interdisciplinary Center of Clinical Research (IZKF), Medical Faculty, Westfaelische Wilhelms-University Muenster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University Tuebingen, Germany. Electronic address: oliver.planz@uni-tuebingen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Planz
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects; D008168:Lung / Q000821:virology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000187:drug effects*; D053139:Oseltamivir / Q000494:pharmacology; D059039:Standard of Care; D019562:Viral Load / Q000187:drug effects
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000998:Antiviral Agents; D001549:Benzamides; D053139:Oseltamivir