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
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
PloS one - 16(2021), 4 vom: 14., Seite e0250019 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Choi, Ryan [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 04.05.2021 Date Revised 16.02.2024 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0250019 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM324406681 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM324406681 | ||
| 003 | DE-627 | ||
| 005 | 20240216232134.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0250019 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1295.xml |
| 035 | |a (DE-627)NLM324406681 | ||
| 035 | |a (NLM)33886614 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Choi, Ryan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.05.2021 | ||
| 500 | |a Date Revised 16.02.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Endoribonucleases |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a nidoviral uridylate-specific endoribonuclease |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 700 | 1 | |a Zhou, Mowei |e verfasserin |4 aut | |
| 700 | 1 | |a Shek, Roger |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Jesse W |e verfasserin |4 aut | |
| 700 | 1 | |a Tillery, Logan |e verfasserin |4 aut | |
| 700 | 1 | |a Craig, Justin K |e verfasserin |4 aut | |
| 700 | 1 | |a Salukhe, Indraneel A |e verfasserin |4 aut | |
| 700 | 1 | |a Hickson, Sarah E |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Neeraj |e verfasserin |4 aut | |
| 700 | 1 | |a James, Rhema M |e verfasserin |4 aut | |
| 700 | 1 | |a Buchko, Garry W |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ruilian |e verfasserin |4 aut | |
| 700 | 1 | |a Huff, Sydney |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Tu-Trinh |e verfasserin |4 aut | |
| 700 | 1 | |a Hurst, Brett L |e verfasserin |4 aut | |
| 700 | 1 | |a Cherry, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Barrett, Lynn K |e verfasserin |4 aut | |
| 700 | 1 | |a Hyde, Jennifer L |e verfasserin |4 aut | |
| 700 | 1 | |a Van Voorhis, Wesley C |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 16(2021), 4 vom: 14., Seite e0250019 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2021 |g number:4 |g day:14 |g pages:e0250019 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0250019 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2021 |e 4 |b 14 |h e0250019 | ||