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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease.
Milligan, Jennifer C; Zeisner, Theresa U; Papageorgiou, George; Joshi, Dhira; Soudy, Christelle; Ulferts, Rachel; Wu, Mary; Lim, Chew Theng; Tan, Kang Wei; Weissmann, Florian; Canal, Berta; Fujisawa, Ryo; Deegan, Tom; Nagaraj, Hema; Bineva-Todd, Ganka; Basier, Clovis; Curran, Joseph F; Howell, Michael; Beale, Rupert; Labib, Karim; O'Reilly, Nicola; Diffley, John F X.
  • 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.
  • Papageorgiou G; Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Joshi D; Peptide Chemistry STP, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Soudy C; Peptide Chemistry STP, 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 STP, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • 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.
  • 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.
  • Fujisawa R; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Deegan T; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Nagaraj H; Peptide Chemistry STP, 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.
  • Basier C; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Curran JF; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Howell M; High Throughput Screening 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.
  • Labib K; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • O'Reilly N; Peptide Chemistry STP, 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): 2499-2515, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1291175
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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ABSTRACT
The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Small Molecule Libraries / Coronavirus 3C 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: Bcj20210197

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Small Molecule Libraries / Coronavirus 3C 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: Bcj20210197