A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.
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 ?M 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.
Mesh Terms:
Adenosine Monophosphate, Alanine, Animals, Antiviral Agents, COVID-19 Drug Treatment, Cell Line, Chlorocebus aethiops, Coronavirus Protease Inhibitors, Humans, Indoles, Pyridines, SARS-CoV-2, Vero Cells, Viral Proteases
Adenosine Monophosphate, Alanine, Animals, Antiviral Agents, COVID-19 Drug Treatment, Cell Line, Chlorocebus aethiops, Coronavirus Protease Inhibitors, Humans, Indoles, Pyridines, SARS-CoV-2, Vero Cells, Viral Proteases
Nat Commun
Date: Jan. 28, 2021
PubMed ID: 33510133
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