Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Corresponding author: Rolf Hilgenfeld

Affiliations: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany; Changchun Discovery Sciences Ltd., 789 Shunda Road, Changchun, Jilin 130012, China; Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany; Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; Institute of Virology, University of Marburg, 35043 Marburg, Germany; German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, University of Marburg, 35043 Marburg, Germany; Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), 38124 Braunschweig, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.

Publication date: this article was published online on Apr 24, 2020

DOI: 10.1126/science.abb3405

Highlights

The main protease (Mpro, also called 3CLpro) is an attractive drug target among coronaviruses because of its essential role in processing the polyproteins that are translated from the viral RNA. In this article, the researchers reported the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. They also further developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

Nomination Reason

The findings reported in this article provides a useful framework for the development of the pyridone-containing inhibitors toward anticoronaviral drugs.

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