Journal Article

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

García-Sastre, Adolfo, White, Kris M., Filler, Renata B., Hanna, Ruth E., Zwaka, Thomas P., Doench, John G., McGovern, Briana L., Luis Rodriguez, M., Yan, Qin, Cai, Wesley L., McNamara, Andrew, Liang, Yu, Kadoch, Cigall, Qin, Yiren, Wilen, Craig B., Alfajaro, Mia Madel, Menasche, Bridget L., Patil, Ajinkya, Peña-Hernández, Mario A., Iwasaki, Akiko, Rosales, Romel, Wei, Jin, Ökten, Arya, Strine, Madison S., DeWeirdt, Peter C., Klein, Jon, Qi, Jun, Collings, Clayton K.

2023

Overview

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. The canonical BRG1/BRM-associated factor (cBAF) complex is recruited by HNF1A/B to angiotensin-converting enzyme 2 (ACE2) enhancers, promoting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inhibition of the catalytic activity of SMARCA4 precludes ACE2 expression and reduces susceptibility to SARS-CoV-1 and major SARS-CoV-2 variants.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/1 / 13/100 / 13/106 / 13/109 / 38 / 38/39 / 45 / 45/15 / 45/91 / 631/208/176 / 631/326/596/4130 / 64/60 / 82 / 82/80 / ACE2 / Agriculture / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Animal Genetics and Genomics / Antiviral agents / Antiviral drugs / Apoptosis / Bioavailability / Biomedical and Life Sciences / Biomedicine / BRG1 protein / Cancer Research / Catalytic activity / Cell lines / Cells / Chromatin / Chromatin remodeling / Cloning / Coronaviruses / COVID-19 / COVID-19 - genetics / CRISPR / Disease resistance / DNA Helicases - genetics / Drug resistance / Enhancers / Enzymes / Epithelial cells / Epithelium / Gene Function / Genomes / Glycoproteins / Human Genetics / Humans / Infections / Localization / Middle East respiratory syndrome / Mutation / Nuclear Proteins - genetics / Pathogenesis / Peptidyl-dipeptidase A / Respiratory diseases / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Sucrose / Therapeutic targets / Transcription factors / Transcription Factors - genetics / Viral diseases / Viruses