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

53 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.

UR - https://www.scopus.com/pages/publications/85127022523

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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