Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection
Jin Wei, Ajinkya Patil, Clayton K. Collings, Mia Madel Alfajaro, Yu Liang, Wesley L. Cai, Madison S. Strine, Renata B. Filler, Peter C. DeWeirdt, Ruth E. Hanna, Bridget L. Menasché, Arya Ökten, Mario A. Peña-Hernández, Jon Klein, Andrew McNamara, Romel Rosales, Briana L McGovern, Marcela Rodriguez, Adolfo García‐Sastre, Kris M. White, Yiren Qin, John G. Doench, Qin Yan, Akiko Iwasaki, Thomas P. Zwaka, Jun Qi, Cigall Kadoch, Craig B. Wilen
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.