2. Academic Validation
  3. Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase

Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase

  • J Med Chem. 2023 Jun 22;66(12):7785-7803. doi: 10.1021/acs.jmedchem.2c02120.
Isha Singh 1,  Fengling Li 2,  Elissa A Fink 1 3,  Irene Chau 2,  Alice Li 4 5,  Annía Rodriguez-Hernández 6,  Isabella Glenn 1,  Francisco J Zapatero-Belinchón 7,  M Luis Rodriguez 8 9,  Kanchan Devkota 2,  Zhijie Deng 10,  Kris White 8 9,  Xiaobo Wan 1,  Nataliya A Tolmachova 11 12,  Yurii S Moroz 13 14,  H Ümit Kaniskan 10,  Melanie Ott 7 15 16 17,  Adolfo García-Sastre 8 9 15 18 19,  Jian Jin 10 15,  Danica Galonić Fujimori 1 6 15,  John J Irwin 1 15,  Masoud Vedadi 2 4 15 5,  Brian K Shoichet 1 15
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, United States.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3 Graduate Program in Biophysics, University of California San Francisco, San Francisco, California 94143, United States.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 5 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • 6 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, United States.
  • 7 Gladstone Institutes, San Francisco, California 94158, United States.
  • 8 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 9 Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 10 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 11 Enamine Ltd, Kyïv 02094, Ukraine.
  • 12 Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Kyïv 02660, Ukraine.
  • 13 National Taras Shevchenko University of Kyïv, Kyïv 01601, Ukraine.
  • 14 Chemspace, Riga LV-1082, Latvia.
  • 15 QBI COVID-19 Research Group (QCRG), San Francisco, California 94158, United States.
  • 16 Department of Medicine, University of California, San Francisco, San Francisco, California 94158, United States.
  • 17 Chan Zuckerberg Biohub, San Francisco, California 94158, United States.
  • 18 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 19 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
PMID: 37294077 DOI: 10.1021/acs.jmedchem.2c02120
Abstract

An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme's SAM site, leading to three inhibitors with IC50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.

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