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
  • 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. [email protected].
  • 22. Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 23. Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].
  • 24. Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA. [email protected].
  • 25. Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. [email protected].
  • 26. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. [email protected].
  • # 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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