학술논문
Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects
Document Type
article
Author
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
Source
The Journal of Clinical Investigation, Vol 133, Iss 19 (2023)
Subject
Language
English
ISSN
1558-8238
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.