A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Vito Thijssen; Daniel L. Hurdiss; Oliver J. Debski-Antoniak; Matthew A. Spence; Charlotte Franck; Alexander Norman; Anupriya Aggarwal; Nadia J. Mokiem; David A.A. van Dongen; Stein W. Vermeir; Minglong Liu; Wentao Li; Marianthi Chatziandreou; Tim Donselaar; Wenjuan Du; Ieva Drulyte; Berend Jan Bosch; Joost Snijder; Stuart G. Turville; Richard J. Payne; Colin J. Jackson; Frank J.M. van Kuppeveld; Seino A.K. Jongkees

doi:10.1073/pnas.2303292120

A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Vito Thijssen
, Daniel L. Hurdiss
, Oliver J. Debski-Antoniak
, Matthew A. Spence
, Charlotte Franck
, Alexander Norman
, Anupriya Aggarwal
, Nadia J. Mokiem
, David A.A. van Dongen
, Stein W. Vermeir
, Minglong Liu
, Wentao Li
, Marianthi Chatziandreou
, Tim Donselaar
, Wenjuan Du
, Ieva Drulyte
, Berend Jan Bosch
, Joost Snijder
, Stuart G. Turville
, Richard J. Payne

Colin J. Jackson, Frank J.M. van Kuppeveld^*, Seino A.K. Jongkees^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used messenger RNA (mRNA) display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor-binding domain, N-terminal domain, and S2 region, distal to the angiotensin-converting enzyme 2 receptor–interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.

Original language	English
Article number	e2303292120
Pages (from-to)	1-7
Number of pages	7
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	26
Early online date	20 Jun 2023
DOIs	https://doi.org/10.1073/pnas.2303292120
Publication status	Published - 27 Jun 2023

Bibliographical note

Funding Information:
made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to D.L.H. V.T. and S.A.K.J. acknowledge general financial support from the department of Chemical Biology and Drug Discovery at Utrecht University. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009).

Funding Information:
ACKNOWLEDGMENTS. We thank J. A. W. Kruijtzer for assistance with peptide synthesis, and the Utrecht Sequencing Facility for providing sequencing service and data. We thank C. A. M. de Haan and Y. Lang for advice and technical assistance. This work was partially funded by the Corona Accelerated R&D in Europe (CARE) project. The CARE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union’s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, the Bill & Melinda Gates Foundation, the Global Health Drug Discovery Institute and the University of Dundee. The content of this publication only reflects the author’s views, and the JU is not responsible for any use that may be made of the information it contains. R.J.P. and C.J.J. received support from Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science. This work

Publisher Copyright:
Copyright © 2023 the Author(s).

Funding

made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to D.L.H. V.T. and S.A.K.J. acknowledge general financial support from the department of Chemical Biology and Drug Discovery at Utrecht University. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). ACKNOWLEDGMENTS. We thank J. A. W. Kruijtzer for assistance with peptide synthesis, and the Utrecht Sequencing Facility for providing sequencing service and data. We thank C. A. M. de Haan and Y. Lang for advice and technical assistance. This work was partially funded by the Corona Accelerated R&D in Europe (CARE) project. The CARE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union’s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, the Bill & Melinda Gates Foundation, the Global Health Drug Discovery Institute and the University of Dundee. The content of this publication only reflects the author’s views, and the JU is not responsible for any use that may be made of the information it contains. R.J.P. and C.J.J. received support from Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science. This work

Funders	Funder number
European Federation of Pharmaceutical Industries and Associations
University of Dundee
department of Chemical Biology and Drug Discovery at Utrecht University
Bill and Melinda Gates Foundation
???publication-publication-funding-organisation-not-added???	184.034.019
Dutch Research Council NWO	024.002.009
Innovative Medicines Initiative	101005077
Horizon 2020 Framework Programme	101005077
SURF	EINF-2453

Keywords

antivirals
Cryo-EM
macrocyclic peptides
mRNA display
SARS-CoV-2

Access to Document

10.1073/pnas.2303292120

Persistent URL (handle)

Persistent link

Cite this

Thijssen, V., Hurdiss, D. L., Debski-Antoniak, O. J., Spence, M. A., Franck, C., Norman, A., Aggarwal, A., Mokiem, N. J., van Dongen, D. A. A., Vermeir, S. W., Liu, M., Li, W., Chatziandreou, M., Donselaar, T., Du, W., Drulyte, I., Bosch, B. J., Snijder, J., Turville, S. G., ... Jongkees, S. A. K. (2023). A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein. Proceedings of the National Academy of Sciences of the United States of America, 120(26), 1-7. Article e2303292120. https://doi.org/10.1073/pnas.2303292120

@article{621d0a17f361467dbce57eb606e47015,

title = "A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein",

abstract = "The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used messenger RNA (mRNA) display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor-binding domain, N-terminal domain, and S2 region, distal to the angiotensin-converting enzyme 2 receptor–interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.",

keywords = "antivirals, Cryo-EM, macrocyclic peptides, mRNA display, SARS-CoV-2",

author = "Vito Thijssen and Hurdiss, \{Daniel L.\} and Debski-Antoniak, \{Oliver J.\} and Spence, \{Matthew A.\} and Charlotte Franck and Alexander Norman and Anupriya Aggarwal and Mokiem, \{Nadia J.\} and \{van Dongen\}, \{David A.A.\} and Vermeir, \{Stein W.\} and Minglong Liu and Wentao Li and Marianthi Chatziandreou and Tim Donselaar and Wenjuan Du and Ieva Drulyte and Bosch, \{Berend Jan\} and Joost Snijder and Turville, \{Stuart G.\} and Payne, \{Richard J.\} and Jackson, \{Colin J.\} and \{van Kuppeveld\}, \{Frank J.M.\} and Jongkees, \{Seino A.K.\}",

note = "Funding Information: made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to D.L.H. V.T. and S.A.K.J. acknowledge general financial support from the department of Chemical Biology and Drug Discovery at Utrecht University. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). Funding Information: ACKNOWLEDGMENTS. We thank J. A. W. Kruijtzer for assistance with peptide synthesis, and the Utrecht Sequencing Facility for providing sequencing service and data. We thank C. A. M. de Haan and Y. Lang for advice and technical assistance. This work was partially funded by the Corona Accelerated R\&D in Europe (CARE) project. The CARE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, the Bill \& Melinda Gates Foundation, the Global Health Drug Discovery Institute and the University of Dundee. The content of this publication only reflects the author{\textquoteright}s views, and the JU is not responsible for any use that may be made of the information it contains. R.J.P. and C.J.J. received support from Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science. This work Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",

year = "2023",

month = jun,

day = "27",

doi = "10.1073/pnas.2303292120",

language = "English",

volume = "120",

pages = "1--7",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "26",

}

Thijssen, V, Hurdiss, DL, Debski-Antoniak, OJ, Spence, MA, Franck, C, Norman, A, Aggarwal, A, Mokiem, NJ, van Dongen, DAA, Vermeir, SW, Liu, M, Li, W, Chatziandreou, M, Donselaar, T, Du, W, Drulyte, I, Bosch, BJ, Snijder, J, Turville, SG, Payne, RJ, Jackson, CJ, van Kuppeveld, FJM & Jongkees, SAK 2023, 'A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 26, e2303292120, pp. 1-7. https://doi.org/10.1073/pnas.2303292120

TY - JOUR

T1 - A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

AU - Thijssen, Vito

AU - Hurdiss, Daniel L.

AU - Debski-Antoniak, Oliver J.

AU - Spence, Matthew A.

AU - Franck, Charlotte

AU - Norman, Alexander

AU - Aggarwal, Anupriya

AU - Mokiem, Nadia J.

AU - van Dongen, David A.A.

AU - Vermeir, Stein W.

AU - Liu, Minglong

AU - Li, Wentao

AU - Chatziandreou, Marianthi

AU - Donselaar, Tim

AU - Du, Wenjuan

AU - Drulyte, Ieva

AU - Bosch, Berend Jan

AU - Snijder, Joost

AU - Turville, Stuart G.

AU - Payne, Richard J.

AU - Jackson, Colin J.

AU - van Kuppeveld, Frank J.M.

AU - Jongkees, Seino A.K.

N1 - Funding Information: made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to D.L.H. V.T. and S.A.K.J. acknowledge general financial support from the department of Chemical Biology and Drug Discovery at Utrecht University. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). Funding Information: ACKNOWLEDGMENTS. We thank J. A. W. Kruijtzer for assistance with peptide synthesis, and the Utrecht Sequencing Facility for providing sequencing service and data. We thank C. A. M. de Haan and Y. Lang for advice and technical assistance. This work was partially funded by the Corona Accelerated R&D in Europe (CARE) project. The CARE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union’s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, the Bill & Melinda Gates Foundation, the Global Health Drug Discovery Institute and the University of Dundee. The content of this publication only reflects the author’s views, and the JU is not responsible for any use that may be made of the information it contains. R.J.P. and C.J.J. received support from Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science. This work Publisher Copyright: Copyright © 2023 the Author(s).

PY - 2023/6/27

Y1 - 2023/6/27

N2 - The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used messenger RNA (mRNA) display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor-binding domain, N-terminal domain, and S2 region, distal to the angiotensin-converting enzyme 2 receptor–interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.

AB - The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used messenger RNA (mRNA) display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor-binding domain, N-terminal domain, and S2 region, distal to the angiotensin-converting enzyme 2 receptor–interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.

KW - antivirals

KW - Cryo-EM

KW - macrocyclic peptides

KW - mRNA display

KW - SARS-CoV-2

UR - https://www.scopus.com/pages/publications/85163922831

UR - https://www.scopus.com/pages/publications/85163922831#tab=citedBy

U2 - 10.1073/pnas.2303292120

DO - 10.1073/pnas.2303292120

M3 - Article

C2 - 37339194

AN - SCOPUS:85163922831

SN - 0027-8424

VL - 120

SP - 1

EP - 7

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 26

M1 - e2303292120

ER -

A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this