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-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M). Two kinds of cyclic γ-amino acids, cis-3-aminocyclobutane carboxylic acid (γ) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ at the fourth position, manifests a 5.2 nM dissociation constant. An M:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ interacts with the S1' catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and M enabled production of a variant with a 5-fold increase in potency.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322702 | PMC |
http://dx.doi.org/10.1038/s41557-023-01205-1 | DOI Listing |
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