SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging

Nat Chem Biol. 2021 Feb;17(2):222-228. doi: 10.1038/s41589-020-00689-z. Epub 2020 Oct 22.

Abstract

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-DTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 µM) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. We visualized active SARS-CoV-2 Mpro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • COVID-19 / diagnostic imaging*
  • COVID-19 / pathology
  • COVID-19 / virology
  • Catalytic Domain
  • Combinatorial Chemistry Techniques
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / chemistry
  • Coronavirus 3C Proteases / genetics
  • Coronavirus 3C Proteases / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Epithelial Cells / ultrastructure
  • Epithelial Cells / virology*
  • Fluorescent Dyes / chemistry
  • Gene Expression
  • Glutamine / chemistry
  • Humans
  • Models, Molecular
  • Nasopharynx / virology
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • Severe acute respiratory syndrome-related coronavirus / drug effects
  • Severe acute respiratory syndrome-related coronavirus / enzymology
  • Substrate Specificity

Substances

  • Antiviral Agents
  • Fluorescent Dyes
  • Protease Inhibitors
  • Glutamine
  • Coronavirus 3C Proteases