Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2023
- Source ID
- 10.1038/s41588-023-01307-z
Entities
People
- Adolfo García-Sastre
- Ajinkya Patil
- Akiko Iwasaki
- Andrew Mcnamara
- Arya Ökten
- Briana L. McGovern
- Bridget L Menasche
- Cigall Kadoch
- Clayton K. Collings
- Craig B Wilen
- Jin Wei
- John G Doench
- Jon Klein
- Jun Qi
- Kris M White
- M. Luis Rodriguez
- Madison S Strine
- Mario A. Peña-hernández
- Mia Madel Alfajaro
- Peter C. DeWeirdt
- Qin Yan
- Renata B. Filler
- Romel Rosales
- Ruth E. Hanna
- Thomas P. Zwaka
- Wesley L. Cai
- Yiren Qin
- Yu Liang
Organizations
- Burroughs Wellcome Fund
- G. Harold & Leila Y. Mathers Foundation
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Science Foundation
- Office of the Director
- Richard and Susan Smith Family Foundation
- United States Department of Defense