Structure-Based Design of a Cyclic Peptide Inhibitor of the SARS-CoV-2 Main Protease

This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (M^pro). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at aC-terminal autolytic cleavage site of M^pro. Synthesis and evaluation of a first-generation cyclic peptide inhibitor reveals that the inhibitor is active against M^proin vitroand is non-toxic toward human cells in culture. The initial hit described in this manuscript, UCI-1, lays the groundwork for the development of additional cyclic peptide inhibitors against M^prowith improved activities.