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Multi-level inhibition of coronavirus replication by chemical ER stress

Mohammed Samer Shaban1, Christin Müller2, Christin Mayr-Buro1

  • 1Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.

Nature Communications
|September 21, 2021
PubMed

Insights

Thapsigargin, an ER stress inducer, effectively inhibits coronavirus replication by targeting key viral mechanisms. This finding suggests thapsigargin as a potential broad-spectrum antiviral drug for coronaviruses (CoVs).

Area of Science:

  • Virology
  • Cell Biology
  • Pharmacology

Background:

  • Coronaviruses (CoVs) pose significant threats as human pathogens.
  • Currently, no specific antiviral treatments are available for CoVs.

Purpose of the Study:

  • To investigate the potential of pharmacological reprogramming of ER stress pathways to suppress CoV replication.
  • To identify specific molecular mechanisms underlying the antiviral effects of thapsigargin.

Main Methods:

  • Utilized thapsigargin, an ER stress inducer, to treat cells infected with various CoVs (HCoV-229E, MERS-CoV, SARS-CoV-2).
  • Assessed viral replication, cellular viability, translational shut-down, and expression of ER stress markers (IRE1α, BiP).
  • Performed proteome-wide analyses to identify host factors involved in the antiviral response.

Main Results:

  • Thapsigargin efficiently inhibited CoV replication across different cell types, including primary human bronchial epithelial cells.
  • The compound reversed virus-induced translational shutdown, improved cell viability, and counteracted CoV-mediated downregulation of IRE1α and BiP.
  • Proteomic analysis identified ER quality control factors (HERPUD1, UBA6, ZNF622) and ER-associated degradation complexes mediating the antiviral state; thapsigargin also blocked CoV-induced autophagic flux.

Conclusions:

  • Thapsigargin targets multiple critical mechanisms essential for CoV replication.
  • This ER stress inducer demonstrates potential as a broad-spectrum antiviral agent against coronaviruses, warranting further development of thapsigargin or its derivatives.

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