4.6 Article

High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity

Journal

PLOS ONE
Volume 16, Issue 4, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0250019

Keywords

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Funding

  1. National Institute of Allergy and Infectious Diseases
  2. National Institutes of Health, Department of Health and Human Services [HHSN272201700059C, 75N93019D00021, 75N93020P00667]
  3. DOE Office of Science through the National Virtual Biotechnology Laboratory
  4. Coronavirus CARES Act
  5. U.S. Department of Energy's Office of Biological and Environmental Research (BER) program located at Pacific Northwest National Laboratory (PNNL)
  6. U.S. Department of Energy [DE-AC05-76RL01830]

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Several compounds with inhibitory effects on SARS-CoV-2 nsp15 endonuclease have been identified through high-throughput screening, including Exebryl-1. Despite the inhibitory concentrations of Exebryl-1 exceeding therapeutic levels, further optimization shows promising potential for its use as an antiviral against SARS-CoV-2.
SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 mu M range in vitro. Furthermore, Exebryl-1, a ss-amyloid anti-aggregation molecule for Alzheimer's therapy, was shown to have antiviral activity between 10 to 66 mu M, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.

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