A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33510133.
- Also identified by DOI 10.1038/s41467-021-20900-6 and PMC identifier 7843602.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 (M<sup>pro</sup>). 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 EC<sub>50</sub> 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 M<sup>pro</sup> and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead M<sup>pro</sup> inhibitor for the development of therapeutics for SARS-CoV-2 infection.
Medical subject headings
- Coronavirus Protease Inhibitors
- SARS-CoV-2
- Viral Proteases
- COVID-19 Drug Treatment