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; Huang, Pei-Tzu; Chiu, Winston; Durán, Verónica; Lo, Chieh-Wen; Kumar, Sathish; Bhalla, Nishank; Leyssen, Pieter; Alem, Farhang; Boghdeh, Niloufar A; Tran, HoangNhu; Cohen, Courtney A; Brown, Jacquelyn A; 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
Source
Journal of Clinical Investigation. 133(19)
Subject
Language
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 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.