Growth Factor Receptor Signaling Inhibition Prevents SARS-CoV-2 Replication

Mol Cell. 2020 Oct 1;80(1):164-174.e4. doi: 10.1016/j.molcel.2020.08.006. Epub 2020 Aug 11.


SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.

Keywords: COVID-19; PI3K; RAS; SARS-CoV-2; TMT; drug repurposing; phosphoproteomics; proteomics; signaling; viral replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antibodies, Neutralizing / therapeutic use
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / immunology
  • Betacoronavirus / pathogenicity
  • Caco-2 Cells
  • Gene Expression Regulation
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / genetics
  • Humans
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinase / genetics*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Receptors, Growth Factor / antagonists & inhibitors
  • Receptors, Growth Factor / genetics*
  • Receptors, Growth Factor / metabolism
  • SARS-CoV-2
  • Signal Transduction
  • Viral Proteins / antagonists & inhibitors
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism
  • Virus Replication / drug effects


  • Adrenal Cortex Hormones
  • Angiotensin-Converting Enzyme Inhibitors
  • Antibodies, Neutralizing
  • Antiviral Agents
  • Phosphoproteins
  • Receptors, Growth Factor
  • Viral Proteins
  • Phosphatidylinositol 3-Kinase
  • Mitogen-Activated Protein Kinases