Browse by author
Lookup NU author(s): Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
γ-Amino acids can play important roles in the biological activities of natural products; however, 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 γ2,4-amino acids (cγAAs) resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (Mpro). Two kinds of cγAAs, 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 Mpro inhibitor (IC50 = 50 nM), GM4, comprising 13 residues with γ1 at the 4th position, manifests a 5.2 nM dissociation constant. An Mpro:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. γ1 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.
Author(s): Miura T, Malla TR, Owen CD, Tumber A, Brewitz L, McDonough MA, Salah E, Terasaka N, Katoh T, Lukacik p, Strain-Damerell C, Mikolajek H, Walsh MA, Kawamura A, Schofield CJ, Suga H
Publication type: Article
Publication status: Published
Journal: Nature Chemistry
Year: 2023
Volume: 15
Pages: 998-1005
Print publication date: 01/07/2023
Online publication date: 22/05/2023
Acceptance date: 14/04/2023
Date deposited: 06/03/2023
ISSN (print): 1755-4330
ISSN (electronic): 1755-4349
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41557-023-01205-1
DOI: 10.1038/s41557-023-01205-1
ePrints DOI: 10.57711/zjxz-as28
Data Access Statement: Coordinates and structure factors have been deposited in the Protein Data Bank (PDB) under accession code 7Z4S. Other data supporting this study are available in the Supplementary Information. Source data are provided with this paper.
Altmetrics provided by Altmetric
