New class of drugs may prevent infection by wide range of COVID-19 variants

Study Title: Pharmacologic disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection

Publication: Nature Genetics https://www.nature.com/articles/s41588-023-01307-z

Dana-Farber Cancer Institute author: Cigall Kadoch, PhD

Summary:

A new class of oral drugs can inhibit a wide range of SARS-CoV-2 variants, researchers report, potentially identifying new antiviral agents providing broad activity against the constantly emerging new strains of the COVID-19 virus. The researchers discovered that the mammalian SWI/SNF (also called BAF) chromatin remodeling complex, a regulator of gene expression –controls the expression of the ACE2, the cellular receptor or “entry point” used by COVID-19 viruses.  When mSWI/SNF complexes were disrupted, the cell could no longer make ACE-2 receptor protein and became resistant to infection by any virus that uses that receptor. Kadoch’s work on mSWI/SNF complexes over the years has led to experimental drugs currently in phase 1 trials as anti-cancer agents. These oral drugs now are looking promising for use in COVID-19, since they can inhibit ACE2 activity and nearly completely block viral infection in multiple cell lines and human lung organoids.

Impact:

The formerly potent array of monoclonal antibody treatments for COVID-19 continue to lose their activity as new less-sensitve variants of the virus appear: indeed, one by one, they have gone off the market. The need for more broadly acting agents against new and drug-resistant viruses is great. With the identification of this new target – a druggable chromatin regulatory complex – inhibition of which prevents infection of host cells, Kadoch and co-author Craig Wilen, MD, PhD, of the Yale Cancer Center have found a promising novel approach to combating the constantly-changing SARS virus.

Funding:

This work was supported by NIH grants K08AI128043, Burroughs Wellcome Fund, Smith Family Foundation, Ludwig Family Foundation, Huffington Foundation, Mathers Foundation, Emergent Ventures Fast Grant, and NIH Director’s New Innovator Award 1DP2CA195762-01.

Contact:  Ellen Berlin, ellen_berlin@dfci.harvard.edu  617-750-8884

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