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 D. Deegan; Ryo Fujisawa; Emma L. Roberts; Clovis Basier; Karim Labib; Rupert Beale; Michael Howell; John F. X. Diffley

doi:10.1042/BCJ20210198

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 D. Deegan, Ryo Fujisawa, Emma L. Roberts, Clovis Basier, Karim Labib, Rupert Beale, Michael Howell, John F. X. Diffley (Lead / Corresponding author)

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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 an 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
Pages (from-to)	2445-2464
Number of pages	20
Journal	Biochemical Journal
Volume	478
Issue number	13
Early online date	11 May 2021
DOIs	https://doi.org/10.1042/BCJ20210198
Publication status	Published - 2 Jul 2021

Keywords

coronavirus
covid-19
methyltransferase
mRNA cap

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1042/BCJ20210198Licence: CC BY

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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. (2021). Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease. Biochemical Journal, 478(13), 2445-2464. https://doi.org/10.1042/BCJ20210198

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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 an 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 = "coronavirus, covid-19, methyltransferase, mRNA cap",

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 Deegan, {Tom D.} 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 = "Funding Information: This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research U.K. (FC001066), the U.K. Medical Research Council (FC001066), and the Wellcome Trust (FC001066). This work was also funded by a Wellcome Trust Senior Investigator Award (106252/Z/14/Z) to J.F.X.D. J.Z. has received funding from a Ph.D. fellowship awarded by Boehringer Ingelheim Fonds. BC and FW have received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement Nos. 895786 and 844211. T.D.D. has received funding from the Wellcome Trust under the Sir Henry Wellcome Postdoctoral Fellowship agreement No. 204678/Z/16/Z. Publisher Copyright: {\textcopyright} 2021 The Author(s).",

year = "2021",

month = jul,

day = "2",

doi = "10.1042/BCJ20210198",

language = "English",

volume = "478",

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Canal, B, McClure, AW, Curran, JF, Wu, M, Ulferts, R, Weissmann, F, Zeng, J, Bertolin, AP, Milligan, JC, Basu, S, Drury, LS, Deegan, TD, 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', Biochemical Journal, vol. 478, no. 13, pp. 2445-2464. https://doi.org/10.1042/BCJ20210198

TY - JOUR

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 D.

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 - Funding Information: This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research U.K. (FC001066), the U.K. Medical Research Council (FC001066), and the Wellcome Trust (FC001066). This work was also funded by a Wellcome Trust Senior Investigator Award (106252/Z/14/Z) to J.F.X.D. J.Z. has received funding from a Ph.D. fellowship awarded by Boehringer Ingelheim Fonds. BC and FW have received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement Nos. 895786 and 844211. T.D.D. has received funding from the Wellcome Trust under the Sir Henry Wellcome Postdoctoral Fellowship agreement No. 204678/Z/16/Z. Publisher Copyright: © 2021 The Author(s).

PY - 2021/7/2

Y1 - 2021/7/2

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 an 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 an 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 - coronavirus

KW - covid-19

KW - methyltransferase

KW - mRNA cap

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U2 - 10.1042/BCJ20210198

DO - 10.1042/BCJ20210198

M3 - Article

C2 - 34198326

SN - 0264-6021

VL - 478

SP - 2445

EP - 2464

JO - Biochemical Journal

JF - Biochemical Journal

IS - 13

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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Molecular Mechanisms of DNA Replication Termination