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

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...

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Veröffentlicht in:JOURNAL OF CLINICAL INVESTIGATION 2023-10, Vol.133 (19)
Hauptverfasser: Saul, Sirle, Huie, Kathleen E, Tindle, Courtney, Sibai, Mamdouh, Ye, Chengjin, Khalil, Ahmed Magdy, Chiem, Kevin, Martinez-Sobrido, Luis, Dye, John M, Pinsky, Benjamin A, Ghosh, Pradipta, Das, Soumita, Solow-Cordero, David E, Jin, Jing, Wikswo, John P, Jochmans, Dirk, Neyts, Johan, De Jonghe, Steven, Narayanan, Aarthi, Einav, Shirit, Karim, Marwah, Ghita, Luca, Huang, Pei-Tzu, Chiu, Winston, Duran, Veronica, Lo, Chieh-Wen, Kumar, Sathish, Bhalla, Nishank, Leyssen, Pieter, Alem, Farhang, Boghdeh, Niloufar A, Tran, Do H.N, Cohen, Courtney A, Brown, Jacquelyn A
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Sprache:eng
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Zusammenfassung: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.
ISSN:0021-9738