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

Front Cell Infect Microbiol. 2023 Oct 26:13:1264983. doi: 10.3389/fcimb.2023.1264983. eCollection 2023.

Abstract

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.

Keywords: EC50; IC50; MEK inhibitor; Raf/MEK/ERK; SARS-CoV-2; antiviral; influenza virus; pandemic preparedness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • COVID-19*
  • Humans
  • Influenza A virus*
  • Influenza, Human* / drug therapy
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase Kinases
  • Pandemics
  • SARS-CoV-2
  • Signal Transduction
  • Virus Replication

Substances

  • Antiviral Agents
  • Mitogen-Activated Protein Kinase Kinases

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors declare that this study received funding from Atriva Therapeutics GmbH (Tuebingen, Germany), licensee of zapnometinib. Furthermore, the authors acknowledge support by the Open Access Publishing Fund of the University of Tübingen.