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Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection.
Wei, Jin; Patil, Ajinkya; Collings, Clayton K; Alfajaro, Mia Madel; Liang, Yu; Cai, Wesley L; Strine, Madison S; Filler, Renata B; DeWeirdt, Peter C; Hanna, Ruth E; Menasche, Bridget L; Ökten, Arya; Peña-Hernández, Mario A; Klein, Jon; McNamara, Andrew; Rosales, Romel; McGovern, Briana L; Luis Rodriguez, M; García-Sastre, Adolfo; White, Kris M; Qin, Yiren; Doench, John G; Yan, Qin; Iwasaki, Akiko; Zwaka, Thomas P; Qi, Jun; Kadoch, Cigall; Wilen, Craig B.
  • Wei J; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Patil A; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Collings CK; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Alfajaro MM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Liang Y; Program in Virology, Harvard Medical School, Boston, MA, USA.
  • Cai WL; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Strine MS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Filler RB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • DeWeirdt PC; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Hanna RE; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Menasche BL; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Ökten A; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Peña-Hernández MA; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Klein J; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • McNamara A; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Rosales R; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • McGovern BL; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Luis Rodriguez M; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • García-Sastre A; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • White KM; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Qin Y; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Doench JG; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Yan Q; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Iwasaki A; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Zwaka TP; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Qi J; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Kadoch C; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • Wilen CB; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Genet ; 55(3): 471-483, 2023 03.
Article in English | MEDLINE | ID: covidwho-2286470
ABSTRACT
Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Nat Genet Journal subject: Genetics, Medical Year: 2023 Document Type: Article Affiliation country: S41588-023-01307-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Nat Genet Journal subject: Genetics, Medical Year: 2023 Document Type: Article Affiliation country: S41588-023-01307-z