Open AccessHigh-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
Author(s) -
Ryan Choi,
Mowei Zhou,
Roger Shek,
Jesse Wilson,
Logan Tillery,
Jonathan M. Craig,
Indraneel Salukhe,
Sarah E. Hickson,
Neeraj Kumar,
Rhema M. James,
Garry W. Buchko,
Ruilian Wu,
Sydney Huff,
Tu-Trinh Nguyen,
Brett L. Hurst,
Sara Cherry,
Lynn K. Barrett,
Jennifer Hyde,
Wesley C. Van Voorhis
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0250019
Subject(s) - drug repositioning , endoribonuclease , repurposing , vero cell , drug discovery , drug , virology , pharmacology , antiviral drug , virtual screening , medicine , chemistry , biology , virus , biochemistry , rnase p , ecology , rna , gene
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.