2. Academic Validation
  3. 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

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

  • PLoS One. 2021 Apr 22;16(4):e0250019. doi: 10.1371/journal.pone.0250019.
Ryan Choi 1,  Mowei Zhou 2,  Roger Shek 1 3,  Jesse W Wilson 2,  Logan Tillery 1 3,  Justin K Craig 1 3,  Indraneel A Salukhe 4,  Sarah E Hickson 4,  Neeraj Kumar 2,  Rhema M James 2,  Garry W Buchko 2 3 5,  Ruilian Wu 6,  Sydney Huff 1,  Tu-Trinh Nguyen 7,  Brett L Hurst 8,  Sara Cherry 9,  Lynn K Barrett 1 3,  Jennifer L Hyde 4,  Wesley C Van Voorhis 1 3 4 10
Affiliations

Affiliations

  • 1 Division of Allergy and Infectious Diseases, Department of Medicine, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington School of Medicine, Seattle, WA, United States of America.
  • 2 Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory (PNNL), Richland, WA, United States of America.
  • 3 Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA, United States of America.
  • 4 Department of Microbiology, University of Washington School of Medicine, Seattle, WA, United States of America.
  • 5 School of Molecular Bioscience, Washington State University, Pullman, WA, United States of America.
  • 6 Bioenergy and Biome Sciences, Los Alamos National Laboratory (LANL), Los Alamos, NM, United States of America.
  • 7 Calibr, a division of The Scripps Research Institute, La Jolla, CA, United States of America.
  • 8 Institute for Antiviral Research, Utah State University, Logan, UT, United States of America.
  • 9 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
  • 10 Department of Global Health, University of Washington, Seattle, WA, United States of America.
PMID: 33886614 DOI: 10.1371/journal.pone.0250019
Abstract

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 μM 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 μM, 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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