2. Academic Validation
  3. Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection

Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection

  • Nat Genet. 2023 Mar;55(3):471-483. doi: 10.1038/s41588-023-01307-z.
Jin Wei # 1 2,  Ajinkya Patil # 3 4 5,  Clayton K Collings 3 4,  Mia Madel Alfajaro 1 2,  Yu Liang 6 7,  Wesley L Cai 8,  Madison S Strine 1 2,  Renata B Filler 1 2,  Peter C DeWeirdt 9,  Ruth E Hanna 9,  Bridget L Menasche 1 2,  Arya Ökten 1 2,  Mario A Peña-Hernández 1 2,  Jon Klein 2,  Andrew McNamara 1 2,  Romel Rosales 10 11,  Briana L McGovern 10 11,  M Luis Rodriguez 10 11,  Adolfo García-Sastre 10 11 12 13 14,  Kris M White 10 11,  Yiren Qin 15 16 17,  John G Doench 9,  Qin Yan 18 19,  Akiko Iwasaki 18 19 20,  Thomas P Zwaka 15 16 17,  Jun Qi 6 7,  Cigall Kadoch 21 22 23,  Craig B Wilen 24 25 26
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
  • 2 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 Program in Virology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 8 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 9 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 10 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 13 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 14 Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 15 Huffington Center for Cell-based Research in Parkinson's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 16 Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 17 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 18 Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • 19 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • 20 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 21 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. cigall_kadoch@dfci.harvard.edu.
  • 22 Broad Institute of MIT and Harvard, Cambridge, MA, USA. cigall_kadoch@dfci.harvard.edu.
  • 23 Howard Hughes Medical Institute, Chevy Chase, MD, USA. cigall_kadoch@dfci.harvard.edu.
  • 24 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA. craig.wilen@yale.edu.
  • 25 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. craig.wilen@yale.edu.
  • 26 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. craig.wilen@yale.edu.
  • # Contributed equally.
PMID: 36894709 DOI: 10.1038/s41588-023-01307-z
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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