Researchers have identified a new class of oral, antiviral drugs that could potentially combat emerging, drug-resistant COVID-19 variants. The team found that host cells carried a druggable chromatin regulatory complex, the inhibition of which could prevent viral infection. These findings could provide an alternative to monoclonal antibody treatments against COVID-19, which are losing their efficacy as new viral variants appear.
The function of mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex in SARS-Cov-2 infection is outlined in the journal Nature Genetics.
“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,” reported Jin Wei, PhD, a postdoctoral associate from Yale School of Medicine, and colleagues.
Currently, authorized direct-acting antivirals target the viral polymerase or viral protease. However viral resistance, drug–drug interactions, and variable efficacy highlight the need for new drug classes with broad activity. Host-directed therapeutics are a particularly promising approach, given their potentially higher barrier to drug resistance, increased breadth of activity, and the likelihood of synergy with direct-acting antiviral drugs.
To investigate further, the team performed a genome-wide CRISPR–Cas9-based screen to identify host genes essential for highly pathogenic coronavirus infection in African green monkey cells.
Many of the top proviral genes for SARS-CoV-2 encoded subunits of the mSWI/SNF complex, an ATP-dependent chromatin remodeling complex that modulates genomic architecture and gene expression. The team showed that functional mSWI/SNF complexes were required for SARS-CoV-2 infection and viral entry in cell lines and three primary human cell types.
Catalytic activity of the subunit gene SMARCA4 was required for mSWI/SNF-driven DNA accessibility at the ACE2 locus, ACE2 expression, and virus susceptibility. Inhibition of mSWI/SNF ATP-dependent chromatin remodeling activity using three different SMARCA4/2-specific orally bioavailable small-molecule inhibitors and degraders reduced ACE2 expression and infection by several SARS-CoV-2 variants.
SMARCA4 inhibitors also inhibited infection of a SARS-CoV-2 strain resistant to the direct-acting antiviral remdesivir, which the researchers say highlights the utility for new antiviral drug classes.
Of note, mSWI/SNF complexes did not regulate mouse ACE2 expression, suggesting species-specific regulation of ACE2 and highlighting the limitations of rodent models in assessing this.
The researchers noted that mSWI/SNF complexes represent the most frequently mutated chromatin regulatory entity in human cancer, with more than a fifth of human cancers bearing mutations. Indeed, SMARCA2/4 ATPase antagonists are currently in Phase I clinical trials for SMARCA2/4-dependent cancers, such as uveal melanoma and acute myeloid leukemia.
The team said: “Taken together, our data suggest that comprehensive studies in humans to evaluate the safety and efficacy of small-molecule antagonists of SMARCA4-mediated mSWI/SNF ATPase activity are warranted and may provide prophylactic and therapeutic benefit for pandemic coronaviruses.”