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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease.
Lim, Chew Theng; Tan, Kang Wei; Wu, Mary; Ulferts, Rachel; Armstrong, Lee A; Ozono, Eiko; Drury, Lucy S; Milligan, Jennifer C; Zeisner, Theresa U; Zeng, Jingkun; Weissmann, Florian; Canal, Berta; Bineva-Todd, Ganka; Howell, Michael; O'Reilly, Nicola; Beale, Rupert; Kulathu, Yogesh; Labib, Karim; Diffley, John F X.
  • Lim CT; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Tan KW; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Wu M; High-Throughput Screening, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Ulferts R; Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Armstrong LA; MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Ozono E; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Drury LS; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Milligan JC; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Zeisner TU; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Zeng J; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Weissmann F; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Canal B; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Bineva-Todd G; Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Howell M; High-Throughput Screening, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • O'Reilly N; Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Beale R; Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Kulathu Y; MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Labib K; MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Diffley JFX; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
Biochem J ; 478(13): 2517-2531, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1290988
Preprint
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ABSTRACT
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 compound 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Small Molecule Libraries / Coronavirus Papain-Like Proteases / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine / Vaccines Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210244

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Small Molecule Libraries / Coronavirus Papain-Like Proteases / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine / Vaccines Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210244