Development of the Safe and Broad-Spectrum Aldehyde and Ketoamide Mpro inhibitors Derived from the Constrained alpha, gamma-AA Peptide Scaffold

SARS-CoV-2 is still wreaking havoc all over the world with surging morbidity and high mortality. The main protease (M-pro) is essential in the replication of SARS-CoV-2, enabling itself an active target for antiviral development. Herein, we reported the design and synthesis of a new class of peptidomimetics-constrained alpha, gamma-AA peptides, based on which a series of aldehyde and ketoamide inhibitors of the M-pro of SARS-CoV-2 were prepared. The lead compounds showed excellent inhibitory activity in the FRET-based M-pro enzymatic assay not only for the M-pro of SARS-CoV-2 but also for SARS-CoV and MERS-CoV, along with HCoVs like HCoV-OC43, HCoV-229E, HCoV-NL63 and HKU1. The X-ray crystallographic results demonstrated that our compounds form a covalent bond with the catalytic Cys145. They also demonstrated effective antiviral activity against live SARS-CoV-2. Overall, the results suggest that alpha, gamma-AA peptide could be a promising molecular scaffold in designing novel M-pro inhibitors of SARS-CoV-2 and other coronaviruses.