Inhibition of SARS-CoV-2 main protease by allosteric drug-binding
Sebastian Günther, Sebastian Günther, Patrick Y. A. Reinke, Yaiza Fernández-García, Julia Lieske, Thomas J. Lane, Helen Mary Ginn, F. Koua, Christiane Ehrt, Wiebke Ewert, D. Oberthüer, Oleksandr M. Yefanov, Susanne Meier, Kristina Lorenzen, Boris Krichel, Janine-Denise Kopicki, Luca Gelisio, W. Brehm, Ilona Dunkel, Brandon Charles Seychell · bioRxiv (Cold Spring Harbor Laboratory) · 2020
Abstract The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M pro ), which is essential for the virus replication and, thus, a potent drug target. 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 binding to M pro . In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.