X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M-pro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M-pro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Automated summary

The study identified 37 compounds that bind to the SARS-CoV-2 main protease through a high-throughput x-ray crystallographic screen of two repurposing drug libraries. Among these compounds, one peptidomimetic and six nonpeptidic compounds showed antiviral activity in cell-based viral reduction assays at nontoxic concentrations. The identification of two allosteric binding sites presents potential targets for drug development against SARS-CoV-2.