A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic
| Autor: | Alissa Campbell, Katherine A. Vernon, Rebecca Thompson, Anna Greka, Julie Roignot, Silvana Bazua-Valenti, Eriene-Heidi Sidhom, Florence F. Wagner, Seth L. Alper, Frederick W.K. Tam, Matthew Racette, Abbe Clark, Michelle Melanson, Ayshwarya Subramanian, Jean Santos, Choah Kim, Estefania Reyes Bricio, Astrid Weins, George C. Tsokos, Jillian L. Shaw, Elizabeth J. Grinkevich, Juliana Coraor, Andrew J. R. Watts, Lucienne V. Ronco, Juan Gutierrez, Keith Keller, Moran Dvela-Levitt, Maria Alimova, Maheswarareddy Emani, Juan Pablo, Abhigyan Satyam, Valeria Padovano, Stephen P. McAdoo, Brian T. Chamberlain, Jamie L. Marshall |
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| Rok vydání: | 2020 |
| Předmět: |
ARDS
Syk MUC1 Pharmacology Lung injury Fostamatinib In vivo Report medicine Lung drug repurposing SARS-CoV-2 business.industry fostamatinib COVID-19 acute respiratory distress syndrome respiratory system medicine.disease respiratory tract diseases ALI Drug repositioning medicine.anatomical_structure acute lung injury Cancer research business medicine.drug |
| Zdroj: | Cell Reports Medicine |
| DOI: | 10.1101/2020.06.30.180380 |
| Popis: | Summary Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI. Graphical Abstract Highlights Elevated MUC1 levels predict the development of acute lung injury (ALI) A high-content screen of 3,713 compounds identifies repurposing candidates R406 removes MUC1 from the apical surface of epithelial cells Fostamatinib treatment reduces MUC1 in a mouse model of lung injury In a high-content screen, Kost-Alimova et al. identify R406, the active metabolite of fostamatinib, as an FDA-approved candidate repurposing compound for the reduction of MUC1 protein levels in lung epithelium in the setting of acute lung injury. |
| Databáze: | OpenAIRE |
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