Influenza A virus replication has a stronger dependency on Raf/MEK/ERK signaling pathway activity than SARS-CoV-2

Frontiers in Cellular and Infection Microbiology

Cellular and Infection Microbiology

Marina Ebensperger¹  Oliver Planz²  Annika Schönsiegel³  Helen Hoffmann³  Julia Koch-Heier³  Hazem Hamza⁴  Michael Schindler⁵  André Schreiber⁶  Stephan Ludwig⁶ 

[1] Atriva Therapeutics GmbH, Tuebingen, Germany;Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany;Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany;Atriva Therapeutics GmbH, Tuebingen, Germany;Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany;Virology Laboratory, Environmental Research Division, National Research Centre, Giza, Egypt;Department of Molecular Virology, Institute for Medical Virology and Epidemiology of Viral Disease, University Hospital Tuebingen, Tuebingen, Germany;Institute of Virology (IVM), Westfaelische Wilhelms Universitaet, Muenster, Muenster, Germany;

关键词: SARS-CoV-2;    influenza virus;    EC;    IC;    Raf/MEK/ERK;    MEK inhibitor;    antiviral;    pandemic preparedness;   

DOI  :  10.3389/fcimb.2023.1264983

 received in 2023-07-21, accepted in 2023-10-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

The recent COVID-19 pandemic again highlighted the urgent need for broad-spectrum antivirals, both for therapeutic use in acute viral infection and for pandemic preparedness in general. The targeting of host cell factors hijacked by viruses during their replication cycle presents one possible strategy for development of broad-spectrum antivirals. By inhibiting the Raf/MEK/ERK signaling pathway, a central kinase cascade of eukaryotic cells, which is being exploited by numerous viruses of different virus phyla, the small-molecule MEK inhibitor zapnometinib has the potential to address this need. We here performed a side-by-side comparison of the antiviral efficacy of zapnometinib against IAV and SARS-CoV-2 to determine the concentration leading to 50% of its effect on the virus (EC50) and the concentration leading to 50% reduction of ERK phosphorylation (IC50) in a comparable manner, using the same experimental conditions. Our results show that the EC50 value and IC50 value of zapnometinib are indeed lower for IAV compared to SARS-CoV-2 using one representative strain for each. The results suggest that IAV’s replication has a stronger dependency on an active Raf/MEK/ERK pathway and, thus, that IAV is more susceptible to treatment with zapnometinib than SARS-CoV-2. With zapnometinib’s favorable outcome in a recent phase II clinical trial in hospitalized COVID-19 patients, the present results are even more promising for an upcoming phase II clinical trial in severe influenza virus infection.

【 授权许可】

Unknown   
Copyright © 2023 Hoffmann, Ebensperger, Schönsiegel, Hamza, Koch-Heier, Schreiber, Ludwig, Schindler and Planz