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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; Sidhom, Eriene-Heidi; Satyam, Abhigyan; Dvela-Levitt, Moran; Melanson, Michelle; Chamberlain, Brian T; Alper, Seth L; Santos, Jean; Gutierrez, Juan; Subramanian, Ayshwarya; Grinkevich, Elizabeth; Bricio, Estefania Reyes; Kim, Choah; Clark, Abbe; Watts, Andrew; Thompson, Rebecca; Marshall, Jamie; Pablo, Juan Lorenzo; Coraor, Juliana; Roignot, Julie; Vernon, Katherine A; Keller, Keith; Campbell, Alissa; Emani, Maheswarareddy; Racette, Matthew; Bazua-Valenti, Silvana; Padovano, Valeria; Weins, Astrid; McAdoo, Stephen P; Tam, Frederick W K; Ronco, Lucienne; Wagner, Florence; Tsokos, George C; Shaw, Jillian L; Greka, Anna.
Afiliação
  • Alimova M; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Sidhom EH; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Satyam A; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Dvela-Levitt M; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Melanson M; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Chamberlain BT; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Alper SL; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Santos J; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Gutierrez J; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Subramanian A; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • Grinkevich E; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Bricio ER; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Kim C; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Clark A; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Watts A; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Thompson R; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Marshall J; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Pablo JL; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Coraor J; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Roignot J; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Vernon KA; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Keller K; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Campbell A; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Emani M; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Racette M; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Bazua-Valenti S; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Padovano V; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Weins A; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • McAdoo SP; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Tam FWK; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Ronco L; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Wagner F; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Tsokos GC; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Shaw JL; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Greka A; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
bioRxiv ; 2020 Jun 30.
Article em En | MEDLINE | ID: mdl-32637960
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: BioRxiv Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: BioRxiv Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos