Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
Stefanie Deinhardt-Emmer,
Laura Jäckel,
Clio Häring,
Sarah Böttcher,
Janine J. Wilden,
Brigitte Glück,
Regine Heller,
Michaela Schmidtke,
Mirijam Koch,
Bettina Löffler,
Stephan Ludwig,
Christina Ehrhardt
Affiliations
Stefanie Deinhardt-Emmer
Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany
Laura Jäckel
Institute of Virology Muenster, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, D-48149 Muenster, Germany
Clio Häring
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Sarah Böttcher
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Janine J. Wilden
Institute of Virology Muenster, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, D-48149 Muenster, Germany
Brigitte Glück
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Regine Heller
Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Michaela Schmidtke
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Mirijam Koch
Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany
Bettina Löffler
Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany
Stephan Ludwig
Institute of Virology Muenster, Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, D-48149 Muenster, Germany
Christina Ehrhardt
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knoell-Str. 2, D-07745 Jena, Germany
Influenza virus (IV) infections are considered to cause severe diseases of the respiratory tract. Beyond mild symptoms, the infection can lead to respiratory distress syndrome and multiple organ failure. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. Interestingly, the virus-supportive function of the cellular phosphatidylinositol 3-kinase (PI3K) suggests that this signaling module may be a potential target for antiviral intervention. In the sense of repurposing existing drugs for new indications, we used Pictilisib, a known PI3K inhibitor to investigate its effect on IV infection, in mono-cell-culture studies as well as in a human chip model. Our results indicate that Pictilisib is a potent inhibitor of IV propagation already at early stages of infection. In a murine model of IV pneumonia, the in vitro key findings were verified, showing reduced viral titers as well as inflammatory response in the lung after delivery of Pictilisib. Our data identified Pictilisib as a promising drug candidate for anti-IV therapies that warrant further studying. These results further led to the conclusion that the repurposing of previously approved substances represents a cost-effective and efficient way for development of novel antiviral strategies.
