Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

Antiviral Res. 2020 Jan:173:104651. doi: 10.1016/j.antiviral.2019.104651. Epub 2019 Nov 18.

Abstract

Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV). We further performed a comparative phosphoproteomic analysis to investigate the mechanism of action of A9 against TGEV infection in vitro. We specifically identified p38 and JNK1, which are the downstream molecules of receptor tyrosine kinases (RTKs) required for efficient TGEV replication, as A9 targets through plaque assays, qRT-PCR and Western blotting assays. p38 and JNK1 inhibitors and RNA interference further showed that the inhibitory activity of A9 against TGEV infection was mainly mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. All these findings indicated that the RTKI A9 directly inhibits TGEV replication and that its inhibitory activity against TGEV replication mainly occurs by targeting p38, which provides vital clues to the design of novel drugs against CoVs.

Keywords: Anti-coronaviral therapy; Comparative phosphoproteomic; Receptor tyrosine kinase inhibitor; Virus-host interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cats
  • Cell Line
  • Cells, Cultured
  • Chlorocebus aethiops
  • Chromatography, Liquid
  • Gastroenteritis, Transmissible, of Swine / drug therapy
  • Gastroenteritis, Transmissible, of Swine / metabolism
  • Gastroenteritis, Transmissible, of Swine / virology
  • High-Throughput Screening Assays
  • Host-Pathogen Interactions*
  • Life Cycle Stages
  • MAP Kinase Signaling System / drug effects*
  • Phosphoproteins / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteomics / methods
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Small Molecule Libraries
  • Swine
  • Tandem Mass Spectrometry
  • Transmissible gastroenteritis virus / drug effects*
  • Vero Cells
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Receptor Protein-Tyrosine Kinases