A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Nat Commun. 2021 Jan 28;12(1):668. doi: 10.1038/s41467-021-20900-6.


Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives
  • Alanine / pharmacology
  • Animals
  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment*
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus Protease Inhibitors / pharmacology*
  • Humans
  • Indoles / pharmacology
  • Pyridines / pharmacology
  • SARS-CoV-2 / drug effects*
  • Vero Cells
  • Viral Proteases / drug effects*
  • Viral Proteases / metabolism


  • 5-chloropyridin-3-yl indoline-4-carboxylate
  • Antiviral Agents
  • Coronavirus Protease Inhibitors
  • Indoles
  • Pyridines
  • remdesivir
  • Adenosine Monophosphate
  • indoline
  • Viral Proteases
  • Alanine