Journal
SCIENCE
Volume 368, Issue 6489, Pages 409-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abb3405
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Funding
- German Center for Infection Research (DZIF) [TTU01, 8011801806, TTU09, 8004709710]
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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.
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