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 unm...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250019&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849469166804795392 |
|---|---|
| author | Ryan Choi Mowei Zhou Roger Shek Jesse W Wilson Logan Tillery Justin K Craig Indraneel A 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 L Hyde Wesley C Van Voorhis |
| author_facet | Ryan Choi Mowei Zhou Roger Shek Jesse W Wilson Logan Tillery Justin K Craig Indraneel A 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 L Hyde Wesley C Van Voorhis |
| author_sort | Ryan Choi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2fda872016ce488d907c534ff63b8ecb |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-2fda872016ce488d907c534ff63b8ecb2025-08-20T03:25:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01164e025001910.1371/journal.pone.0250019High-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.Ryan ChoiMowei ZhouRoger ShekJesse W WilsonLogan TilleryJustin K CraigIndraneel A SalukheSarah E HicksonNeeraj KumarRhema M JamesGarry W BuchkoRuilian WuSydney HuffTu-Trinh NguyenBrett L HurstSara CherryLynn K BarrettJennifer L HydeWesley C Van VoorhisSARS-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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250019&type=printable |
| spellingShingle | Ryan Choi Mowei Zhou Roger Shek Jesse W Wilson Logan Tillery Justin K Craig Indraneel A 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 L Hyde Wesley C Van Voorhis 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 |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250019&type=printable |
| work_keys_str_mv | AT ryanchoi highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT moweizhou highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT rogershek highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT jessewwilson highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT logantillery highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT justinkcraig highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT indraneelasalukhe highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT sarahehickson highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT neerajkumar highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT rhemamjames highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT garrywbuchko highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT ruilianwu highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT sydneyhuff highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT tutrinhnguyen highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT brettlhurst highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT saracherry highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT lynnkbarrett highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT jenniferlhyde highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity AT wesleycvanvoorhis highthroughputscreeningofthereframepandemicboxandcovidboxdrugrepurposinglibrariesagainstsarscov2nsp15endoribonucleasetoidentifysmallmoleculeinhibitorsofviralactivity |