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Cyclic β^2,3-amino acids improve the serum stability of macrocyclic peptide inhibitors targeting the SARS-CoV-2 main protease

Lookup NU author(s): Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Due to their constrained conformations, cyclic β^2,3-amino acids (cβAA) are key building blocks that can fold peptides into compact and rigid structures, improving peptidase resistance and binding affinity to target proteins, due to their constrained conformations. Although the translation efficiency of cβAAs is generally low, our engineered tRNA, referred to as tRNA^Pro1E2, enabled efficient incorporation of cβAAs into peptide libraries using the flexible in vitro translation (FIT) system. Here we report on the design and application of a macrocyclic peptide library incorporating three kinds of cβAAs: (1R,2S)-2-aminocyclopentane carboxylic acid (β¹), (1S,2S)-2-aminocyclohexane carboxylic acid (β²), and (1R,2R)-2-aminocyclopentane carboxylic acid. This library was applied to an in vitro selection against the SARS-CoV-2 main protease (M^pro). The resultant peptides, BM3 and BM7, bearing one β² and two β¹, exhibited potent inhibitory activities with IC₅₀ values of 40 nM and 20 nM, respectively. BM3 and BM7 also showed remarkable serum stability with half-lives of 48 h and >168 h, respectively. Notably, BM3A and BM7A, wherein the cβAAs were substituted with alanine, lost their inhibitory activities against M^pro and displayed substantially shorter serum half-lives. This observation underscores the significant contribution of cβAA to the activity and stability of peptides. Overall, our results highlight the potential of cβAA in generating potent and highly stable macrocyclic peptides with drug-like properties.

Publication metadata

Author(s): Miura T, Malla TR, Brewitz L, Tumber A, Salah E, Lee KJ, Terasaka N, Owen CD, Strain-Damerell C, Lukacik P, Walsh MA, Kawamura A, Schofield CJ, Katoh T, Suga H

Publication type: Article

Publication status: Published

Journal: Bulletin of the Chemical Society of Japan

Year: 2024

Volume: 97

Issue: 5

Print publication date: 01/05/2024

Online publication date: 06/03/2024

Acceptance date: 10/02/2024

Date deposited: 05/04/2024

ISSN (electronic): 1348-0634

Publisher: Oxford University Press

URL: https://doi.org/10.1093/bulcsj/uoae018

DOI: 10.1093/bulcsj/uoae018

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