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
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.
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- OSTI Identifier:
- 1779341
- Alternate Identifier(s):
- OSTI ID: 1806308
- Report Number(s):
- PNNL-SA-159108
Journal ID: ISSN 1932-6203; 10.1371/journal.pone.0250019
- Grant/Contract Number:
- AC05-76RL01830; HHSN272201700059C; 75N93019D00021
- Resource Type:
- Published Article
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Name: PLoS ONE Journal Volume: 16 Journal Issue: 4; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; structural biology; structure-based drug discovery; COVID-19; native mass spectrometry; molecular modeling and simulation
Citation Formats
Choi, Ryan, Zhou, Mowei, Shek, Roger, Wilson, Jesse W., Tillery, Logan, Craig, Justin K., Salukhe, Indraneel A., Hickson, Sarah E., Kumar, Neeraj, James, Rhema M., Buchko, Garry W., Wu, Ruilian, Huff, Sydney, Nguyen, Tu-Trinh, Hurst, Brett L., Cherry, Sara, Barrett, Lynn K., Hyde, Jennifer L., Van Voorhis, Wesley C., and Wlodawer, ed., Alexander. 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. United States: N. p., 2021.
Web. doi:10.1371/journal.pone.0250019.
Choi, Ryan, Zhou, Mowei, Shek, Roger, Wilson, Jesse W., Tillery, Logan, Craig, Justin K., Salukhe, Indraneel A., Hickson, Sarah E., Kumar, Neeraj, James, Rhema M., Buchko, Garry W., Wu, Ruilian, Huff, Sydney, Nguyen, Tu-Trinh, Hurst, Brett L., Cherry, Sara, Barrett, Lynn K., Hyde, Jennifer L., Van Voorhis, Wesley C., & Wlodawer, ed., Alexander. 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. United States. https://doi.org/10.1371/journal.pone.0250019
Choi, Ryan, Zhou, Mowei, Shek, Roger, Wilson, Jesse W., Tillery, Logan, Craig, Justin K., Salukhe, Indraneel A., Hickson, Sarah E., Kumar, Neeraj, James, Rhema M., Buchko, Garry W., Wu, Ruilian, Huff, Sydney, Nguyen, Tu-Trinh, Hurst, Brett L., Cherry, Sara, Barrett, Lynn K., Hyde, Jennifer L., Van Voorhis, Wesley C., and Wlodawer, ed., Alexander. Thu .
"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". United States. https://doi.org/10.1371/journal.pone.0250019.
@article{osti_1779341,
title = {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},
author = {Choi, Ryan and Zhou, Mowei and Shek, Roger and Wilson, Jesse W. and Tillery, Logan and Craig, Justin K. and Salukhe, Indraneel A. and Hickson, Sarah E. and Kumar, Neeraj and James, Rhema M. and Buchko, Garry W. and Wu, Ruilian and Huff, Sydney and Nguyen, Tu-Trinh and Hurst, Brett L. and Cherry, Sara and Barrett, Lynn K. and Hyde, Jennifer L. and Van Voorhis, Wesley C. and Wlodawer, ed., Alexander},
abstractNote = {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.},
doi = {10.1371/journal.pone.0250019},
journal = {PLoS ONE},
number = 4,
volume = 16,
place = {United States},
year = {Thu Apr 22 00:00:00 EDT 2021},
month = {Thu Apr 22 00:00:00 EDT 2021}
}
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