Discovery of a novel allosteric binding site in the SARS-2 protease

Our partner site Fraunhofer ITMP in Hamburg was involved in a large research project with more than 100 partners. In order to find drug candidates against SARS-CoV-2, the consortium performed a large-scale X-ray crystallographic screen of the SARS-CoV-2 main protease (Mpro), which is essential for viral replication, against two repurposing libraries containing 5953 unique compounds.

In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, the screen tested already approved drugs, and drugs in clinical trials. From the three-dimensional protein structures, 37 compounds were identified as specific binders to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. Two allosteric binding sites were identified, representing attractive targets for drug development against SARS-CoV-2.

Publication date: April 2, 2021

DOI: 10.1126/science.abf7945