Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

TLDR

The COVID‑19 pandemic caused by SARS‑CoV‑2 has highlighted the main protease (Mpro) as a key drug target due to its essential role in viral polyprotein processing. The authors modified a previously designed inhibitor by incorporating a P3‑P2 amide bond into a pyridone ring, extending its plasma half‑life. Crystallographic analysis of unliganded and inhibitor‑bound Mpro guided the optimization of an α‑ketoamide that potently inhibits the protease, shows pronounced lung tropism, and is suitable for inhalation delivery.

Abstract

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 (Mpro, also called 3CLpro) 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 Mpro 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 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.