Development of the Safe and Broad‐Spectrum Aldehyde and Ketoamide Mpro inhibitors Derived from the Constrained α, γ‐AA Peptide Scaffold

Abstract

AbstractSARS‐CoV‐2 is still wreaking havoc all over the world with surging morbidity and high mortality. The main protease (Mpro) 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 α, γ‐AA peptides, based on which a series of aldehyde and ketoamide inhibitors of the Mpro of SARS‐CoV‐2 were prepared. The lead compounds showed excellent inhibitory activity in the FRET‐based Mpro enzymatic assay not only for the Mpro 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 α, γ‐AA peptide could be a promising molecular scaffold in designing novel Mpro inhibitors of SARS‐CoV‐2 and other coronaviruses.