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

?-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of ?-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic ?2,4-amino acids resulted in the discovery of very potent inhibitors of the ...
SARS-CoV-2 main protease (Mpro). Two kinds of cyclic ?2,4-amino acids, cis-3-aminocyclobutane carboxylic acid (?1) and (1R,3S)-3-aminocyclopentane carboxylic acid (?2), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent Mpro inhibitor (half-maximal inhibitory concentration?=?50?nM), GM4, comprising 13 residues with ?1 at the fourth position, manifests a 5.2?nM dissociation constant. An Mpro:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The ?1 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 Mpro enabled production of a variant with a 5-fold increase in potency.
Mesh Terms:
Amino Acids, Antiviral Agents, COVID-19, Carboxylic Acids, Peptides, Protease Inhibitors, Protein Conformation, SARS-CoV-2
Nat Chem
Date: Jul. 01, 2023
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