The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (M(pro), 3CL(pro)), due to 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 alpha-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. Based on the 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.
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