Journal article
In vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-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, 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 5.8MB, Terms of use)
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- Publisher copy:
- 10.1038/s41557-023-01205-1
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Chemistry More from this journal
- Volume:
- 15
- Pages:
- 998–1005
- Publication date:
- 2023-05-22
- Acceptance date:
- 2023-04-14
- DOI:
- EISSN:
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1755-4349
- ISSN:
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1755-4330
- Language:
-
English
- Keywords:
- Pubs id:
-
1331038
- Local pid:
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pubs:1331038
- Deposit date:
-
2023-03-02
- ARK identifier:
Terms of use
- Copyright holder:
- Miura et al
- Copyright date:
- 2023
- Rights statement:
- ©2023 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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