Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease
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- Berta Canal
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Allison W. McClure
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Joseph F. Curran
- Cell Cycle Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Mary Wu
- High Throughput Screening, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Rachel Ulferts
- Cell Biology of Infection Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Florian Weissmann
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Jingkun Zeng
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Agustina P. Bertolin
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Jennifer C. Milligan
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Souradeep Basu
- Cell Cycle Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Lucy S. Drury
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Tom D. Deegan
- The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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- Ryo Fujisawa
- The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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- Emma L. Roberts
- Cell Cycle Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Clovis Basier
- Cell Cycle Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Karim Labib
- The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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- Rupert Beale
- Cell Biology of Infection Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- Michael Howell
- High Throughput Screening, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
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- John F.X. Diffley
- Chromosome Replication Laboratory, the Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Biochemical Journal
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Biochemical Journal 478 (13), 2445-2464, 2021-07-02
Portland Press Ltd.