Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

Berta Canal; Allison W. McClure; Joseph F. Curran; Mary Wu; Rachel Ulferts; Florian Weissmann; Jingkun Zeng; Agustina P. Bertolin; Jennifer C. Milligan; Souradeep Basu; Lucy S. Drury; Tom Deegan; Ryo Fujisawa; Emma L. Roberts; Clovis Basier; Karim Labib; Rupert Beale; Michael Howell; John F. X. Diffley

doi:10.1101/2021.04.07.438812

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

Berta Canal, Allison W. McClure, Joseph F. Curran, Mary Wu, Rachel Ulferts, Florian Weissmann, Jingkun Zeng, Agustina P. Bertolin, Jennifer C. Milligan, Souradeep Basu, Lucy S. Drury, Tom Deegan, Ryo Fujisawa, Emma L. Roberts, Clovis Basier, Karim Labib, Rupert Beale, Michael Howell, John F. X. Diffley (Lead / Corresponding author)

MRC PPU

Research output: Working paper/Preprint › Preprint

Abstract

SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.

Original language	English
Publisher	BioRxiv
Pages	1-41
Number of pages	41
DOIs	https://doi.org/10.1101/2021.04.07.438812
Publication status	Published - 8 Apr 2021

Keywords

biochemistry

Access to Document

10.1101/2021.04.07.438812Licence: CC BY

1 Article

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease
Canal, B., McClure, A. W., Curran, J. F., Wu, M., Ulferts, R., Weissmann, F., Zeng, J., Bertolin, A. P., Milligan, J. C., Basu, S., Drury, L. S., Deegan, T. D., Fujisawa, R., Roberts, E. L., Basier, C., Labib, K., Beale, R., Howell, M. & Diffley, J. F. X. (Lead / Corresponding author), 2 Jul 2021, In: Biochemical Journal. 478, 13, p. 2445-2464 20 p.
Research output: Contribution to journal › Article › peer-review

Open Access
File
29 Citations (Scopus)

170 Downloads (Pure)

Cite this

Canal, B., McClure, A. W., Curran, J. F., Wu, M., Ulferts, R., Weissmann, F., Zeng, J., Bertolin, A. P., Milligan, J. C., Basu, S., Drury, L. S., Deegan, T., Fujisawa, R., Roberts, E. L., Basier, C., Labib, K., Beale, R., Howell, M., & Diffley, J. F. X. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease. (pp. 1-41). BioRxiv. https://doi.org/10.1101/2021.04.07.438812

@techreport{406d609fff8a4237b61c6e43bee0f853,

title = "Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease",

abstract = "SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.",

keywords = "biochemistry",

author = "Berta Canal and McClure, {Allison W.} and Curran, {Joseph F.} and Mary Wu and Rachel Ulferts and Florian Weissmann and Jingkun Zeng and Bertolin, {Agustina P.} and Milligan, {Jennifer C.} and Souradeep Basu and Drury, {Lucy S.} and Tom Deegan and Ryo Fujisawa and Roberts, {Emma L.} and Clovis Basier and Karim Labib and Rupert Beale and Michael Howell and Diffley, {John F. X.}",

note = "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.",

year = "2021",

month = apr,

day = "8",

doi = "10.1101/2021.04.07.438812",

language = "English",

pages = "1--41",

publisher = "BioRxiv",

address = "United States",

type = "WorkingPaper",

institution = "BioRxiv",

}

Canal, B, McClure, AW, Curran, JF, Wu, M, Ulferts, R, Weissmann, F, Zeng, J, Bertolin, AP, Milligan, JC, Basu, S, Drury, LS, Deegan, T, Fujisawa, R, Roberts, EL, Basier, C, Labib, K, Beale, R, Howell, M & Diffley, JFX 2021 'Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease' BioRxiv, pp. 1-41. https://doi.org/10.1101/2021.04.07.438812

TY - UNPB

T1 - Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

AU - Canal, Berta

AU - McClure, Allison W.

AU - Curran, Joseph F.

AU - Wu, Mary

AU - Ulferts, Rachel

AU - Weissmann, Florian

AU - Zeng, Jingkun

AU - Bertolin, Agustina P.

AU - Milligan, Jennifer C.

AU - Basu, Souradeep

AU - Drury, Lucy S.

AU - Deegan, Tom

AU - Fujisawa, Ryo

AU - Roberts, Emma L.

AU - Basier, Clovis

AU - Labib, Karim

AU - Beale, Rupert

AU - Howell, Michael

AU - Diffley, John F. X.

N1 - The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.

PY - 2021/4/8

Y1 - 2021/4/8

N2 - SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.

AB - SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.

KW - biochemistry

U2 - 10.1101/2021.04.07.438812

DO - 10.1101/2021.04.07.438812

M3 - Preprint

SP - 1

EP - 41

BT - Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

PB - BioRxiv

ER -

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

Abstract

Keywords

Access to Document

Fingerprint

Research output

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease

Cite this