Previous studies have identified the the main protease (Mpro, 3CLpro) of coronaviruses as a potential drug target because it has an essential role in processing the polyproteins translated from viral RNA. The authors examined the X-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. They developed this from a previously designed inhibitor but incorporated the P3-P2 amide bond into a pyridone ring to enhance its half-life in plasma. Using the structure, the authors were able to further develop the lead compound into a potent inhibitor of SARS-CoV-2 Mpro Pharmacokinetics suggest a pronounced lung tropism, making it suitable for administration by inhalation.
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