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

Stefanie Deinhardt-Emmer,Regine Heller,Sarah Böttcher,Mirijam Koch,Clio Häring,Brigitte Glück,Janine J Wilden,Christina Ehrhardt,Laura Jäckel,Michaela Schmidtke,Stephan Ludwig,Bettina Löffler

doi:10.3390/biom11060808

Stefanie Deinhardt-Emmer, Regine Heller + Show 10 more

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https://doi.org/10.3390/biom11060808

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Abstract

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.

Highlights

Pictilisib Treatment Leads to an Efficient Inhibition of Influenza Virus Replication in
We elucidated if Pictilisib may exhibit inhibitory potential on Influenza virus (IV) propagation
Cells were pre-incubated with the indicated concentrations of Pictilisib or solvent control (DMSO) for 30 min and infected with IV

Summary

Introduction

Seasonal influenza virus (IV) epidemics and recurring pandemics engender respiratory illness and frequently severe disease symptoms, high mortality rates, and substantial healthcare costs [1,2]. The most efficient way to protect against annual IV epidemics is vaccination [3]. Coverage is low, efficiency is variable, and vaccinations will not confer protection against newly emerging IV subtypes [4]. Licensed therapeutics in Germany are currently restricted to one substance class that targets the viral neuraminidase, since M2 channel blockers are no longer recommended against IV [5]. A new drug class, represented by Baloxavir marboxil, a polymerase inhibitor, is so far only approved in Japan

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