The Journal of Clinical Investigation (Oct 2023)

Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

  • Sirle Saul,
  • Marwah Karim,
  • Luca Ghita,
  • Pei-Tzu Huang,
  • Winston Chiu,
  • Verónica Durán,
  • Chieh-Wen Lo,
  • Sathish Kumar,
  • Nishank Bhalla,
  • Pieter Leyssen,
  • Farhang Alem,
  • Niloufar A. Boghdeh,
  • Do H.N. Tran,
  • Courtney A. Cohen,
  • Jacquelyn A. Brown,
  • Kathleen E. Huie,
  • Courtney Tindle,
  • Mamdouh Sibai,
  • Chengjin Ye,
  • Ahmed Magdy Khalil,
  • Kevin Chiem,
  • Luis Martinez-Sobrido,
  • John M. Dye,
  • Benjamin A. Pinsky,
  • Pradipta Ghosh,
  • Soumita Das,
  • David E. Solow-Cordero,
  • Jing Jin,
  • John P. Wikswo,
  • Dirk Jochmans,
  • Johan Neyts,
  • Steven De Jonghe,
  • Aarthi Narayanan,
  • Shirit Einav

Journal volume & issue
Vol. 133, no. 19

Abstract

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Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2–induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

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