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Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice

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 m...

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Autores principales: Deinhardt-Emmer, Stefanie, Jäckel, Laura, Häring, Clio, Böttcher, Sarah, Wilden, Janine J., Glück, Brigitte, Heller, Regine, Schmidtke, Michaela, Koch, Mirijam, Löffler, Bettina, Ludwig, Stephan, Ehrhardt, Christina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228449/
https://www.ncbi.nlm.nih.gov/pubmed/34072389
http://dx.doi.org/10.3390/biom11060808
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author Deinhardt-Emmer, Stefanie
Jäckel, Laura
Häring, Clio
Böttcher, Sarah
Wilden, Janine J.
Glück, Brigitte
Heller, Regine
Schmidtke, Michaela
Koch, Mirijam
Löffler, Bettina
Ludwig, Stephan
Ehrhardt, Christina
author_facet Deinhardt-Emmer, Stefanie
Jäckel, Laura
Häring, Clio
Böttcher, Sarah
Wilden, Janine J.
Glück, Brigitte
Heller, Regine
Schmidtke, Michaela
Koch, Mirijam
Löffler, Bettina
Ludwig, Stephan
Ehrhardt, Christina
author_sort Deinhardt-Emmer, Stefanie
collection PubMed
description 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.
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spelling pubmed-82284492021-06-26 Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice Deinhardt-Emmer, Stefanie Jäckel, Laura Häring, Clio Böttcher, Sarah Wilden, Janine J. Glück, Brigitte Heller, Regine Schmidtke, Michaela Koch, Mirijam Löffler, Bettina Ludwig, Stephan Ehrhardt, Christina Biomolecules Article 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. MDPI 2021-05-29 /pmc/articles/PMC8228449/ /pubmed/34072389 http://dx.doi.org/10.3390/biom11060808 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Deinhardt-Emmer, Stefanie
Jäckel, Laura
Häring, Clio
Böttcher, Sarah
Wilden, Janine J.
Glück, Brigitte
Heller, Regine
Schmidtke, Michaela
Koch, Mirijam
Löffler, Bettina
Ludwig, Stephan
Ehrhardt, Christina
Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title_full Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title_fullStr Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title_full_unstemmed Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title_short Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice
title_sort inhibition of phosphatidylinositol 3-kinase by pictilisib blocks influenza virus propagation in cells and in lungs of infected mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228449/
https://www.ncbi.nlm.nih.gov/pubmed/34072389
http://dx.doi.org/10.3390/biom11060808
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