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7074534 
Journal Article 
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors 
Zhang, L; Lin, D; Sun, X; Curth, Ute; Drosten, C; Sauerhering, L; Becker, S; Rox, K; Hilgenfeld, R; , 
2020 
1 
Science
ISSN: 0036-8075
EISSN: 1095-9203 
AMER ASSOC ADVANCEMENT SCIENCE 
WASHINGTON 
409-+ 
32198291 
WOS:000528513300041 
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 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. On the basis of the unliganded structure, we 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.