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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease.
Canal, Berta; Fujisawa, Ryo; McClure, Allison W; Deegan, Tom D; Wu, Mary; Ulferts, Rachel; Weissmann, Florian; Drury, Lucy S; Bertolin, Agustina P; Zeng, Jingkun; Beale, Rupert; Howell, Michael; Labib, Karim; Diffley, John F X.
  • Canal B; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Fujisawa R; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • McClure AW; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Deegan TD; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, 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.
  • Weissmann F; 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.
  • Bertolin AP; Chromosome Replication 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.
  • Beale R; Cell Biology of Infection Laboratory, 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.
  • Labib K; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, 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): 2465-2479, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1290092
Preprint
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ABSTRACT
SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonuclease inhibitors, and we identified and validated NSC95397 as an inhibitor of nsp15 endoribonuclease in vitro. Although NSC95397 did not inhibit SARS-CoV-2 growth in VERO E6 cells, further studies will be required to determine the effect of nsp15 inhibition on host immune evasion.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Nonstructural Proteins / Drug Evaluation, Preclinical / Endoribonucleases / Small Molecule Libraries / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210199

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Nonstructural Proteins / Drug Evaluation, Preclinical / Endoribonucleases / Small Molecule Libraries / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210199