SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78

Nicholas Ross Johnson; Craig Pattinson; Kate Burgoyne; Karolin Hijazi; Wael E Houssen; Bruce Milne

doi:10.1002/cbic.202300789

SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78

Nicholas Ross Johnson, Craig Pattinson, Kate Burgoyne, Karolin Hijazi^* (Corresponding Author), Wael E Houssen^* (Corresponding Author), Bruce Milne^* (Corresponding Author)

^*Corresponding author for this work

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

Abstract

The human glucose-regulated protein GRP78 is a human chaperone that translocactes to the cell surface when cells are under stress. Theoretical studies suggested it could be involved in SARSCoV-2 virus entry to cells. In this work, we used in vitro surface plasmon resonance-based assays to show that human GRP78 indeed binds to SARS-CoV-2 spike protein. We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480-488 of the SARS-CoV-2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78. Consistent with the greater infectiousness of the Omicron variant, the Omicron-derived peptide displays slower dissociation from the target protein. Both peptides significantly inhibit the binding of wild-type S1 protein to the human protein GRP78 suggesting that further development of these cyclic peptide motifs may provide a viable route to novel anti-SARS-CoV-2 agents.

Original language	English
Article number	e202300789
Journal	ChemBioChem
Early online date	13 Apr 2024
DOIs	https://doi.org/10.1002/cbic.202300789
Publication status	E-pub ahead of print - 13 Apr 2024

Bibliographical note

Open Access via the Wiley Agreement

This project was supported by a fellowship grant from the EPSRC (No. EP/S027246/1, W.E.H.), a training grant from the BBSRC (BB/V509206/1, W. E. H) and an award from the GCRF Covid-19 Response (W.E.H. and K.H). N.J. is funded by the IBioIC CTP PhD programme. B.F.M. acknowledges national funds from the Portuguese FCT – Fundação para a Ciência e a Tecnologia, I.P., within the projects UIDB/04564/2020 and UIDP/04564/2020. B.F.M. thanks the Portuguese National Network for Advanced Computing (rnca.fccn.pt/en/) for the award of 1.2 million hours of computer time (2021.09804.CPCA) and the Laboratory for Advanced Computing of the University of Coimbra (www.uc.pt/lca/) for technical support and administration of the high-performance computer architecture used in this work.

Data Availability Statement

No data availability statement.

Keywords

GRP78
BiP
SARS-CoV-2
HSPA5
Cyclic peptides

Access to Document

10.1002/cbic.202300789Licence: CC BY

Data From SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78
Johnson, N. R. (Creator), Pattinson, C. (Creator), Burgoyne, K. (Creator), Hijazi, K. (Creator), Houssen, W. E. (Creator) & Milne, B. F. (Creator), University of Aberdeen, 13 Apr 2024
DOI: 10.1002/cbic.202300789
Dataset

Cite this

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abstract = "The human glucose-regulated protein GRP78 is a human chaperone that translocactes to the cell surface when cells are under stress. Theoretical studies suggested it could be involved in SARSCoV-2 virus entry to cells. In this work, we used in vitro surface plasmon resonance-based assays to show that human GRP78 indeed binds to SARS-CoV-2 spike protein. We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480-488 of the SARS-CoV-2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78. Consistent with the greater infectiousness of the Omicron variant, the Omicron-derived peptide displays slower dissociation from the target protein. Both peptides significantly inhibit the binding of wild-type S1 protein to the human protein GRP78 suggesting that further development of these cyclic peptide motifs may provide a viable route to novel anti-SARS-CoV-2 agents.",

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note = "Open Access via the Wiley Agreement This project was supported by a fellowship grant from the EPSRC (No. EP/S027246/1, W.E.H.), a training grant from the BBSRC (BB/V509206/1, W. E. H) and an award from the GCRF Covid-19 Response (W.E.H. and K.H). N.J. is funded by the IBioIC CTP PhD programme. B.F.M. acknowledges national funds from the Portuguese FCT – Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia, I.P., within the projects UIDB/04564/2020 and UIDP/04564/2020. B.F.M. thanks the Portuguese National Network for Advanced Computing (rnca.fccn.pt/en/) for the award of 1.2 million hours of computer time (2021.09804.CPCA) and the Laboratory for Advanced Computing of the University of Coimbra (www.uc.pt/lca/) for technical support and administration of the high-performance computer architecture used in this work. ",

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AU - Houssen, Wael E

AU - Milne, Bruce

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N2 - The human glucose-regulated protein GRP78 is a human chaperone that translocactes to the cell surface when cells are under stress. Theoretical studies suggested it could be involved in SARSCoV-2 virus entry to cells. In this work, we used in vitro surface plasmon resonance-based assays to show that human GRP78 indeed binds to SARS-CoV-2 spike protein. We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480-488 of the SARS-CoV-2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78. Consistent with the greater infectiousness of the Omicron variant, the Omicron-derived peptide displays slower dissociation from the target protein. Both peptides significantly inhibit the binding of wild-type S1 protein to the human protein GRP78 suggesting that further development of these cyclic peptide motifs may provide a viable route to novel anti-SARS-CoV-2 agents.

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SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78

Abstract

Bibliographical note

Data Availability Statement

Keywords

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Datasets

Data From SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78

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