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

Jason Johansen-Leete; Sven Ullrich; Sarah E. Fry; Rebecca Frkic; Max J. Bedding; Anupriya Aggarwal; Anneliese S. Ashhurst; Kasuni B. Ekanayake; Mithun C. Mahawaththa; Vishnu M. Sasi; Stephanie Luedtke; Daniel J. Ford; Anthony J. O'Donoghue; Toby Passioura; Mark Larance; Gottfried Otting; Stuart Turville; Colin J. Jackson; Christoph Nitsche; Richard J. Payne

doi:10.1039/D1SC06750H

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

Jason Johansen-Leete,

^ab Sven Ullrich,

^c Sarah E. Fry,^ab Rebecca Frkic,^cd Max J. Bedding,

^ab Anupriya Aggarwal,^e Anneliese S. Ashhurst,^abf Kasuni B. Ekanayake,

^cd Mithun C. Mahawaththa,

^cd Vishnu M. Sasi,^cd Stephanie Luedtke,

^g Daniel J. Ford,^ab Anthony J. O'Donoghue,

^g Toby Passioura,

^abhi Mark Larance,^ij Gottfried Otting,

^cd Stuart Turville,^e Colin J. Jackson,^cd Christoph Nitsche

*^c and Richard J. Payne

*^ab

Author affiliations

* Corresponding authors

^a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
E-mail: richard.payne@sydney.edu.au

^b Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW 2006, Australia

^c Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
E-mail: christoph.nitsche@anu.edu.au

^d Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT 2601, Australia

^e Kirby Institute, Sydney, NSW 2052, Australia

^f School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia

^g Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

^h School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia

ⁱ Sydney Analytical, The University of Sydney, Sydney, NSW 2006, Australia

^j Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia

Abstract

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M^pro) 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 M^pro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M^pro 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 M^pro 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.

This article is part of the themed collection: Most popular 2022 chemical biology articles

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

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