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Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp3 Papain-like Protease

View ORCID ProfileChew Theng Lim, View ORCID ProfileKang Wei Tan, View ORCID ProfileMary Wu, View ORCID ProfileRachel Ulferts, View ORCID ProfileLee A. Armstrong, View ORCID ProfileEiko Ozono, View ORCID ProfileLucy S. Drury, View ORCID ProfileJennifer C. Milligan, View ORCID ProfileTheresa U. Zeisner, View ORCID ProfileJingkun Zeng, View ORCID ProfileFlorian Weissmann, View ORCID ProfileBerta Canal, View ORCID ProfileGanka Bineva-Todd, View ORCID ProfileMichael Howell, View ORCID ProfileNicola O’Reilly, View ORCID ProfileRupert Beale, View ORCID ProfileYogesh Kulathu, View ORCID ProfileKarim Labib, View ORCID ProfileJohn F.X Diffley
doi: https://doi.org/10.1101/2021.04.07.438804
Chew Theng Lim
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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  • ORCID record for Chew Theng Lim
Kang Wei Tan
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Mary Wu
2High-Throughput Screening, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Rachel Ulferts
3Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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  • ORCID record for Rachel Ulferts
Lee A. Armstrong
6MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
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Eiko Ozono
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Lucy S. Drury
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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  • ORCID record for Lucy S. Drury
Jennifer C. Milligan
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Theresa U. Zeisner
4Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Jingkun Zeng
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Florian Weissmann
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Berta Canal
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Ganka Bineva-Todd
5Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Michael Howell
2High-Throughput Screening, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Nicola O’Reilly
5Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Rupert Beale
3Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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Yogesh Kulathu
6MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
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Karim Labib
6MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
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John F.X Diffley
1Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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  • ORCID record for John F.X Diffley
  • For correspondence: john.diffley@crick.ac.uk
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Summary

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom chemical library from which we identified Dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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.
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Posted April 08, 2021.
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Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp3 Papain-like Protease
Chew Theng Lim, Kang Wei Tan, Mary Wu, Rachel Ulferts, Lee A. Armstrong, Eiko Ozono, Lucy S. Drury, Jennifer C. Milligan, Theresa U. Zeisner, Jingkun Zeng, Florian Weissmann, Berta Canal, Ganka Bineva-Todd, Michael Howell, Nicola O’Reilly, Rupert Beale, Yogesh Kulathu, Karim Labib, John F.X Diffley
bioRxiv 2021.04.07.438804; doi: https://doi.org/10.1101/2021.04.07.438804
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Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp3 Papain-like Protease
Chew Theng Lim, Kang Wei Tan, Mary Wu, Rachel Ulferts, Lee A. Armstrong, Eiko Ozono, Lucy S. Drury, Jennifer C. Milligan, Theresa U. Zeisner, Jingkun Zeng, Florian Weissmann, Berta Canal, Ganka Bineva-Todd, Michael Howell, Nicola O’Reilly, Rupert Beale, Yogesh Kulathu, Karim Labib, John F.X Diffley
bioRxiv 2021.04.07.438804; doi: https://doi.org/10.1101/2021.04.07.438804

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