biostudies-literatureUnknown368(6489)Zhang LThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M^pro, also called 3CL^pro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M^pro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M^pro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.Science (New York, N.Y.)409-412https://www.ebi.ac.uk/biostudies/studies/S-EPMC7164518biostudies-literatureCrystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.PMC7164518Rox KHilgenfeld RLin DDrosten CZhang LSauerhering LSun XCurth UBecker SfalseCrystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M^pro, also called 3CL^pro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M^pro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M^pro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.2020-01-01T00:00:00Z2020 Apr2022-02-09T15:49:08.13Z2020-05-22T17:36:06ZS-EPMC71645183219829110.1126/science.abb3405