Pan-ErbB inhibition protects from SARS-CoV-2 replication, inflammation, and injury

Effective therapies are needed to combat emerging viruses. Seventeen candidates that rescue cells from SARS-CoV-2-induced lethality and target diverse functions emerged in a screen of 4,413 compounds. Among the hits was lapatinib, an approved inhibitor of the ErbB family of receptor tyrosine kinases. Lapatinib and other pan-ErbB inhibitors suppress replication of SARS-CoV-2 and unrelated viruses with a high barrier to resistance. ErbB4, but not lapatinibs cancer targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry and Venezuelan equine encephalitis virus infection and is a molecular target mediating lapatinibs antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in acute and chronic lung injury downstream of ErbBs (p38-MAPK, MEK/ERK, and AKT/mTOR), pro-inflammatory cytokine production, and epithelial barrier injury. These findings reveal regulation of viral infection, inflammation, and tissue injury via ErbBs and propose approved candidates to counteract these effects with implications for coronaviruses and unrelated viruses.