In vitro selection of macrocyclic peptide inhibitors containing cyclic γ^2,4-amino acids targeting the SARS-CoV-2 main protease.

ABSTRACT: γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ^2,4-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M^pro). Two kinds of cyclic γ^2,4-amino acids, cis-3-aminocyclobutane carboxylic acid (γ¹) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ²), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M^pro inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ¹ at the

SUBMITTER: Miura T 

PROVIDER: S-EPMC10322702 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature