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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase.
Zeng, Jingkun; Weissmann, Florian; Bertolin, Agustina P; Posse, Viktor; Canal, Berta; Ulferts, Rachel; Wu, Mary; Harvey, Ruth; Hussain, Saira; Milligan, Jennifer C; Roustan, Chloe; Borg, Annabel; McCoy, Laura; Drury, Lucy S; Kjaer, Svend; McCauley, John; Howell, Michael; Beale, Rupert; Diffley, John F X.
  • 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.
  • Bertolin AP; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Posse V; 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.
  • Ulferts R; Cell Biology of Infection 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.
  • Harvey R; World Influenza Centre, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Hussain S; World Influenza Centre, 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.
  • Roustan C; Structural Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Borg A; Structural Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • McCoy L; Division of Infection and Immunity, University College London, London WC1E 6BT, U.K.
  • Drury LS; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Kjaer S; Structural Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • McCauley J; World Influenza Centre, 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.
  • Beale R; Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Diffley JFX; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
Biochem J ; 478(13): 2405-2423, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1292181
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ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Nonstructural Proteins / RNA Helicases / Drug Evaluation, Preclinical / Small Molecule Libraries / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine / Vaccines / Variants Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210201

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Nonstructural Proteins / RNA Helicases / Drug Evaluation, Preclinical / Small Molecule Libraries / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine / Vaccines / Variants Limits: Animals Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210201