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, 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^*

^*Corresponding author for this work

Research School of Chemistry

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3826-3836
Number of pages	11
Journal	Chemical Science
Volume	13
Issue number	13
DOIs	https://doi.org/10.1039/d1sc06750h
Publication status	Published - 28 Feb 2022

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Johansen-Leete, J., Ullrich, S., Fry, S. E., Frkic, R., Bedding, M. J., Aggarwal, A., Ashhurst, A. S., Ekanayake, K. B., Mahawaththa, M. C., Sasi, V. M., Luedtke, S., Ford, D. J., O'Donoghue, A. J., Passioura, T., Larance, M., Otting, G., Turville, S., Jackson, C. J., Nitsche, C., & Payne, R. J. (2022). Antiviral cyclic peptides targeting the main protease of SARS-CoV-2. Chemical Science, 13(13), 3826-3836. https://doi.org/10.1039/d1sc06750h

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title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Royal Society of Chemistry",

year = "2022",

month = feb,

day = "28",

doi = "10.1039/d1sc06750h",

language = "English",

volume = "13",

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Johansen-Leete, J, Ullrich, S, Fry, SE, Frkic, R, Bedding, MJ, Aggarwal, A, Ashhurst, AS, Ekanayake, KB, Mahawaththa, MC, Sasi, VM, Luedtke, S, Ford, DJ, O'Donoghue, AJ, Passioura, T, Larance, M, Otting, G, Turville, S, Jackson, CJ , Nitsche, C & Payne, RJ 2022, 'Antiviral cyclic peptides targeting the main protease of SARS-CoV-2', Chemical Science, vol. 13, no. 13, pp. 3826-3836. https://doi.org/10.1039/d1sc06750h

TY - JOUR

T1 - Antiviral cyclic peptides targeting the main protease of SARS-CoV-2

AU - Johansen-Leete, Jason

AU - Ullrich, Sven

AU - Fry, Sarah E.

AU - Frkic, Rebecca

AU - Bedding, Max J.

AU - Aggarwal, Anupriya

AU - Ashhurst, Anneliese S.

AU - Ekanayake, Kasuni B.

AU - Mahawaththa, Mithun C.

AU - Sasi, Vishnu M.

AU - Luedtke, Stephanie

AU - Ford, Daniel J.

AU - O'Donoghue, Anthony J.

AU - Passioura, Toby

AU - Larance, Mark

AU - Otting, Gottfried

AU - Turville, Stuart

AU - Jackson, Colin J.

AU - Nitsche, Christoph

AU - Payne, Richard J.

PY - 2022/2/28

Y1 - 2022/2/28

N2 - 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.

AB - 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.

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U2 - 10.1039/d1sc06750h

DO - 10.1039/d1sc06750h

M3 - Article

SN - 2041-6520

VL - 13

SP - 3826

EP - 3836

JO - Chemical Science

JF - Chemical Science

IS - 13

ER -

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

Abstract

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