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  2. Discovery of pan-ErbB inhibitors protecting from SARS-CoV-2 replication, inflammation, and lung injury by a drug repurposing screen

Discovery of pan-ErbB inhibitors protecting from SARS-CoV-2 replication, inflammation, and lung injury by a drug repurposing screen

  • bioRxiv. 2021 Jun 15;2021.05.15.444128. doi: 10.1101/2021.05.15.444128.
Sirle Saul Marwah Karim Pei-Tzu Huang Luca Ghita Winston Chiu Sathish Kumar Nishank Bhalla Pieter Leyssen Courtney A Cohen Kathleen Huie Courtney Tindle Mamdouh Sibai Benjamin A Pinsky Soumita Das Pradipta Ghosh John M Dye David E Solow-Cordero Jing Jin Dirk Jochmans Johan Neyts Aarthi Narayanan Steven De Jonghe Shirit Einav
Abstract

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 lapatinib's Cancer targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry and encephalitis alphavirus Infection and is a molecular target mediating lapatinib's antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in non-infectious acute lung injury and fibrosis 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 lung injury via ErbBs and propose approved candidates to counteract these effects with implications for pandemic coronaviruses and unrelated viruses.

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