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.

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

“…TP53 loss does not affect the entry of vesicular stomatitis virus (VSV) pseudoviral particles (VSVpp) displaying the SARS-CoV-1, SARS-CoV-2, or MERS-CoV coronavirus spike glycoproteins, in support of its effects on the cytopathic effect downstream of viral entry ( Fig. 1H ) 47,48 . Finally, TP53 protein levels are increased upon SARS-CoV-2 infection and less so upon HKU5-SARS-CoV-1-S and MERS-CoV infections, consistent with its regulation via protein stability 49 ( Fig.…”

“…Host-directed therapies, such as 25-hydroxycholesterol, imatinib, and CMK, may also disrupt SASP activation by inhibiting cell-cell fusion 74,[81][82][83][84][85] . Furthermore, since ACE2 is required not only for SARS-CoV-2 viral entry but also for cell-cell fusion 20,23,78 , suppressing endogenous ACE2 expression such as through SMARCA4/2 or FXR inhibition could also prevent TP53 stabilization 48,130 . Altogether, we propose a mechanism for how SARS-CoV-2 and its fusogenic variants differentially modulate the host cell response to infection and activate senescence via differences in the spike protein.…”

Marine Sponge-Derived Secondary Metabolites Modulate SARS-CoV-2 Entry Mechanisms

“…The cBAF (canonical BRG1/ BRM-associated factor complexes) help the SARS-CoV-2 virus infect cells by enabling SMARCA4's catalytic activity, which is necessary for chromatin accessibility at the ACE2 locus. This affects ACE2 expression and makes the cells more susceptible to the virus [31]. We showed that BRG1 and HMGB1 are both expressed in the nucleus of VeroE6 cells (▶Fig.…”

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

“…Given the critical role of ACE2 in mediating infection with some coronaviruses (4,(30)(31)(32)(33), elucidating how ACE2 is physiologically regulated could provide a broad therapeutic strategy against ACE2dependent viral infections. In light of this, recent studies have identified AR, FXR, and the mSWI/SNF chromatin remodeling complex as key players in the transcriptional regulation of ACE2 expression, and small-molecule inhibitors targeting these proteins were highlighted to be effective in restricting SARS-CoV-2 infection (27)(28)(29). However, the expression of both AR and FXR exhibits tissue and cell specificity (fig.…”

“…Nonetheless, apart from direct targeting of the RNA virus, it is theoretically postulated that drugs capable of eliminating the crucial host receptor required for viral entry, instead of inhibiting a viral protein or blocking viral-host interactions, could potentially diminish the likelihood of viral escape mutations. In this respect, small molecules targeting the androgen receptor (AR) and farnesoid X receptor (FXR), as well as the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex, were reported to suppress ACE2 transcription, thereby restricting SARS-CoV-2 infection ( 27 – 29 ). In the present study, we characterized the pivotal role of ubiquitin-specific peptidase 2 (USP2) as a physiological deubiquitinase of ACE2.…”