Researchers identify the mSWI/SNF chromatin remodeling complex as a host-directed drug target for SARS-CoV-2 infection NatureGenet YaleMed harvardmed broadinstitute UPMC chromatin COVID19 coronavirus covid SARSCoV2 infection
By Neha MathurMar 14 2023Reviewed by Danielle Ellis, B.Sc. In a recent article published in Nature Genetics, researchers showed that mammalian SWItch/Sucrose Non-Fermentable chromatin remodeling complexes represent a potential class of host-directed broad-acting severe acute respiratory syndrome coronavirus 2 therapeutic target.
Background Amid the continuous emergence of new SARS-CoV-2 variants with immune-evading potential, there is an urgent need for new prophylactic and therapeutic antiviral strategies against current and yet-to-emerge coronaviruses . However, it requires an in-depth understanding of molecular and cellular-level virus–host interactions.
Seven CoVs, including SARS, SARS-CoV1, SARS-CoV-2, and HCoV-NL63, use host angiotensin-converting enzyme 2 as a receptor to attach their spike glycoprotein, a process in which several proteases, e.g., transmembrane protease serine 2 mediate proteolytic processing. Then, the virus enters the host cell and releases its ribonucleic acid in the cytoplasm to establish infection via the assembly of transcription complexes for further budding.
More than 20% of human cancers bear mutations in mSWI/SNF complexes. Thus, many drugs inhibiting mSWI/SNF family complexes are under evaluation in clinical trials across many cancer-related indications. However, there is a shortage of data on how mSWI/SNF complexes mediate SARS-CoV-2 infection. Although ACE2 gene expression is a determinant of SARS-CoV-2 pathogenesis, dynamic regulation of it at the molecular level is incompletely understood, especially the effect of transient ablation of ACE2 in adult animals. The screen used in this study helped the researchers identify SMARCA4 as the second top hit after ACE2 in A549 and Huh7.5 cells. The other two screens using only Huh7.5 cells did not detect ACE2 as a statistically significant hit.
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