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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.

ABSTRACT: Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. 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 MUC1 protein abundance. Our screen identified 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 reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

SUBMITTER: Alimova M

PROVIDER: S-EPMC7337390 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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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.

Alimova Maria M Sidhom Eriene-Heidi EH Satyam Abhigyan A Dvela-Levitt Moran M Melanson Michelle M Chamberlain Brian T BT Alper Seth L SL Santos Jean J Gutierrez Juan J Subramanian Ayshwarya A Grinkevich Elizabeth E Bricio Estefania Reyes ER Kim Choah C Clark Abbe A Watts Andrew A Thompson Rebecca R Marshall Jamie J Pablo Juan Lorenzo JL Coraor Juliana J Roignot Julie J Vernon Katherine A KA Keller Keith K Campbell Alissa A Emani Maheswarareddy M Racette Matthew M Bazua-Valenti Silvana S Padovano Valeria V Weins Astrid A McAdoo Stephen P SP Tam Frederick W K FWK Ronco Lucienne L Wagner Florence F Tsokos George C GC Shaw Jillian L JL Greka Anna A

bioRxiv : the preprint server for biology 20200630

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic ...[more]

PMID: 32637960

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Dataset Information

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.

Publications

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.

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