Issue 13, 2022

Antiviral cyclic peptides targeting the main protease of SARS-CoV-2

Abstract

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

Graphical abstract: Antiviral cyclic peptides targeting the main protease of SARS-CoV-2

Supplementary files

Article information

Article type
Edge Article
Submitted
02 dec 2021
Accepted
28 feb 2022
First published
28 feb 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 3826-3836

Antiviral cyclic peptides targeting the main protease of SARS-CoV-2

J. Johansen-Leete, S. Ullrich, S. E. Fry, R. Frkic, M. J. Bedding, A. Aggarwal, A. S. Ashhurst, K. B. Ekanayake, M. C. Mahawaththa, V. M. Sasi, S. Luedtke, D. J. Ford, A. J. O'Donoghue, T. Passioura, M. Larance, G. Otting, S. Turville, C. J. Jackson, C. Nitsche and R. J. Payne, Chem. Sci., 2022, 13, 3826 DOI: 10.1039/D1SC06750H

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