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 ...
(Mpro), 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 Mpro 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.
Mesh Terms:
Allosteric Site, Animals, Antiviral Agents, Catalytic Domain, Chlorocebus aethiops, Coronavirus 3C Proteases, Crystallography, X-Ray, Drug Development, Drug Evaluation, Preclinical, Protease Inhibitors, SARS-CoV-2, Vero Cells, Virus Replication
Science
Date: Dec. 07, 2020
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