The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

Cell Mol Life Sci. 2022 Jan 10;79(1):65. doi: 10.1007/s00018-021-04085-1.

Abstract

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air-liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.

Keywords: ATR-002; Antiviral drug; COVID-19; MEK1/2-inhibitor; Raf/MEK/ERK; SARS-CoV-2.

MeSH terms

  • A549 Cells
  • Adult
  • Animals
  • Antiviral Agents / pharmacology*
  • COVID-19 / drug therapy*
  • COVID-19 / metabolism
  • Cell Line
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cytokines / metabolism
  • Fenamates / pharmacology*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-3,4-difluorobenzoic acid
  • Antiviral Agents
  • Cytokines
  • Fenamates
  • Protein Kinase Inhibitors
  • MAP2K2 protein, human
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human