학술논문
Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects.
Document Type
Article
Author
Saul, Sirle; Karim, Marwah; Ghita, Luca; Pei-Tzu Huang; Chiu, Winston; Durán, Verónica; Chieh-Wen Lo; Kumar, Sathish; Bhalla, Nishank; Leyssen, Pieter; Alem, Farhang; Boghdeh, Niloufar A.; Tran, Do H. N.; Cohen, Courtney A.; Brown, Jacquelyn A.; Huie, Kathleen E.; Tindle, Courtney; Sibai, Mamdouh; Chengjin Ye; Khalil, Ahmed Magdy
Source
Subject
*VENEZUELAN equine encephalomyelitis
*SOFT tissue injuries
*KINASES
*LIFE cycles (Biology)
*ENCEPHALITIS viruses
*INFLAMMATION
*
*
*
*
*
Language
ISSN
0021-9738
Abstract
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 directacting 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 SARSCoV-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 bloodbrain 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. [ABSTRACT FROM AUTHOR]