tetano
Editor, Senior Moderator
Nat Genet
. 2023 Mar 9.
doi: 10.1038/s41588-023-01307-z. Online ahead of print.
Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection
Jin Wei[SUP] #[/SUP][SUP] 1 2 [/SUP], Ajinkya Patil[SUP] #[/SUP][SUP] 3 4 5 [/SUP], Clayton K Collings[SUP] 3 4 [/SUP], Mia Madel Alfajaro[SUP] 1 2 [/SUP], Yu Liang[SUP] 6 7 [/SUP], Wesley L Cai[SUP] 8 [/SUP], Madison S Strine[SUP] 1 2 [/SUP], Renata B Filler[SUP] 1 2 [/SUP], Peter C DeWeirdt[SUP] 9 [/SUP], Ruth E Hanna[SUP] 9 [/SUP], Bridget L Menasche[SUP] 1 2 [/SUP], Arya Ökten[SUP] 1 2 [/SUP], Mario A Peña-Hernández[SUP] 1 2 [/SUP], Jon Klein[SUP] 2 [/SUP], Andrew McNamara[SUP] 1 2 [/SUP], Romel Rosales[SUP] 10 11 [/SUP], Briana L McGovern[SUP] 10 11 [/SUP], M Luis Rodriguez[SUP] 10 11 [/SUP], Adolfo García-Sastre[SUP] 10 11 12 13 14 [/SUP], Kris M White[SUP] 10 11 [/SUP], Yiren Qin[SUP] 15 16 17 [/SUP], John G Doench[SUP] 9 [/SUP], Qin Yan[SUP] 18 19 [/SUP], Akiko Iwasaki[SUP] 18 19 20 [/SUP], Thomas P Zwaka[SUP] 15 16 17 [/SUP], Jun Qi[SUP] 6 7 [/SUP], Cigall Kadoch[SUP] 21 22 23 [/SUP], Craig B Wilen[SUP] 24 25 26 [/SUP]
Affiliations
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.
. 2023 Mar 9.
doi: 10.1038/s41588-023-01307-z. Online ahead of print.
Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection
Jin Wei[SUP] #[/SUP][SUP] 1 2 [/SUP], Ajinkya Patil[SUP] #[/SUP][SUP] 3 4 5 [/SUP], Clayton K Collings[SUP] 3 4 [/SUP], Mia Madel Alfajaro[SUP] 1 2 [/SUP], Yu Liang[SUP] 6 7 [/SUP], Wesley L Cai[SUP] 8 [/SUP], Madison S Strine[SUP] 1 2 [/SUP], Renata B Filler[SUP] 1 2 [/SUP], Peter C DeWeirdt[SUP] 9 [/SUP], Ruth E Hanna[SUP] 9 [/SUP], Bridget L Menasche[SUP] 1 2 [/SUP], Arya Ökten[SUP] 1 2 [/SUP], Mario A Peña-Hernández[SUP] 1 2 [/SUP], Jon Klein[SUP] 2 [/SUP], Andrew McNamara[SUP] 1 2 [/SUP], Romel Rosales[SUP] 10 11 [/SUP], Briana L McGovern[SUP] 10 11 [/SUP], M Luis Rodriguez[SUP] 10 11 [/SUP], Adolfo García-Sastre[SUP] 10 11 12 13 14 [/SUP], Kris M White[SUP] 10 11 [/SUP], Yiren Qin[SUP] 15 16 17 [/SUP], John G Doench[SUP] 9 [/SUP], Qin Yan[SUP] 18 19 [/SUP], Akiko Iwasaki[SUP] 18 19 20 [/SUP], Thomas P Zwaka[SUP] 15 16 17 [/SUP], Jun Qi[SUP] 6 7 [/SUP], Cigall Kadoch[SUP] 21 22 23 [/SUP], Craig B Wilen[SUP] 24 25 26 [/SUP]
Affiliations
- 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.