A Ligand Selection Strategy Identifies Chemical Probes Targeting the Proteases of SARS-CoV-2

Angew Chem Int Ed Engl. 2021 Mar 15;60(12):6799-6806. doi: 10.1002/anie.202016113. Epub 2021 Jan 28.

Abstract

Activity-based probes are valuable tools for chemical biology. However, finding probes that specifically target the active site of an enzyme remains a challenging task. Herein, we present a ligand selection strategy that allows to rapidly tailor electrophilic probes to a target of choice and showcase its application for the two cysteine proteases of SARS-CoV-2 as proof of concept. The resulting probes were specific for the active site labeling of 3CLpro and PLpro with sufficient selectivity in a live cell model as well as in the background of a native human proteome. Exploiting the probes as tools for competitive profiling of a natural product library identified salvianolic acid derivatives as promising 3CLpro inhibitors. We anticipate that our ligand selection strategy will be useful to rapidly develop customized probes and discover inhibitors for a wide range of target proteins also beyond corona virus proteases.

Keywords: ABPP; chemical probes; enzyme inhibitors; labeling; proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Coronavirus 3C Proteases / chemistry*
  • Coronavirus 3C Proteases / metabolism
  • Coronavirus Papain-Like Proteases / chemistry*
  • Coronavirus Papain-Like Proteases / metabolism
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Hep G2 Cells
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Probe Techniques*
  • Molecular Probes / chemistry*
  • Molecular Structure
  • Proof of Concept Study
  • Protein Binding
  • SARS-CoV-2 / enzymology*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Ligands
  • Molecular Probes
  • Small Molecule Libraries
  • 3C-like protease, SARS coronavirus
  • Coronavirus Papain-Like Proteases
  • papain-like protease, SARS-CoV-2
  • Coronavirus 3C Proteases