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Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease.
Ma, Chunlong; Sacco, Michael Dominic; Hurst, Brett; Townsend, Julia Alma; Hu, Yanmei; Szeto, Tommy; Zhang, Xiujun; Tarbet, Bart; Marty, Michael Thomas; Chen, Yu; Wang, Jun.
  • Ma C; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA.
  • Sacco MD; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
  • Hurst B; Institute for Antiviral Research, Utah State University, Logan, UT, 84322, USA.
  • Townsend JA; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA.
  • Hu Y; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA.
  • Szeto T; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA.
  • Zhang X; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA.
  • Tarbet B; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
  • Marty MT; Institute for Antiviral Research, Utah State University, Logan, UT, 84322, USA.
  • Chen Y; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA.
  • Wang J; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA.
Cell Res ; 30(8): 678-692, 2020 08.
Article in English | MEDLINE | ID: covidwho-599672
Preprint
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ABSTRACT
A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known substrate-based peptidomimetic Mpro inhibitors. A complex crystal structure of SARS-CoV-2 Mpro with GC-376, determined at 2.15 Å resolution with three protomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by Mpro. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Pyrrolidines / Virus Replication / Proline / Glycoproteins / Viral Nonstructural Proteins / Coronavirus Infections / Betacoronavirus Topics: Vaccines Limits: Animals / Humans Language: English Journal: Cell Res Year: 2020 Document Type: Article Affiliation country: S41422-020-0356-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Pyrrolidines / Virus Replication / Proline / Glycoproteins / Viral Nonstructural Proteins / Coronavirus Infections / Betacoronavirus Topics: Vaccines Limits: Animals / Humans Language: English Journal: Cell Res Year: 2020 Document Type: Article Affiliation country: S41422-020-0356-z