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Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for...

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Autores principales: Yang, Kailu, Wang, Chuchu, Kreutzberger, Alex J. B., Ojha, Ravi, Kuivanen, Suvi, Couoh-Cardel, Sergio, Muratcioglu, Serena, Eisen, Timothy J., White, K. Ian, Held, Richard G., Subramanian, Subu, Marcus, Kendra, Pfuetzner, Richard A., Esquivies, Luis, Doyle, Catherine A., Kuriyan, John, Vapalahti, Olli, Balistreri, Giuseppe, Kirchhausen, Tom, Brunger, Axel T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546559/
https://www.ncbi.nlm.nih.gov/pubmed/36122200
http://dx.doi.org/10.1073/pnas.2210990119
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author Yang, Kailu
Wang, Chuchu
Kreutzberger, Alex J. B.
Ojha, Ravi
Kuivanen, Suvi
Couoh-Cardel, Sergio
Muratcioglu, Serena
Eisen, Timothy J.
White, K. Ian
Held, Richard G.
Subramanian, Subu
Marcus, Kendra
Pfuetzner, Richard A.
Esquivies, Luis
Doyle, Catherine A.
Kuriyan, John
Vapalahti, Olli
Balistreri, Giuseppe
Kirchhausen, Tom
Brunger, Axel T.
author_facet Yang, Kailu
Wang, Chuchu
Kreutzberger, Alex J. B.
Ojha, Ravi
Kuivanen, Suvi
Couoh-Cardel, Sergio
Muratcioglu, Serena
Eisen, Timothy J.
White, K. Ian
Held, Richard G.
Subramanian, Subu
Marcus, Kendra
Pfuetzner, Richard A.
Esquivies, Luis
Doyle, Catherine A.
Kuriyan, John
Vapalahti, Olli
Balistreri, Giuseppe
Kirchhausen, Tom
Brunger, Axel T.
author_sort Yang, Kailu
collection PubMed
description Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein.
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spelling pubmed-95465592022-10-08 Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein Yang, Kailu Wang, Chuchu Kreutzberger, Alex J. B. Ojha, Ravi Kuivanen, Suvi Couoh-Cardel, Sergio Muratcioglu, Serena Eisen, Timothy J. White, K. Ian Held, Richard G. Subramanian, Subu Marcus, Kendra Pfuetzner, Richard A. Esquivies, Luis Doyle, Catherine A. Kuriyan, John Vapalahti, Olli Balistreri, Giuseppe Kirchhausen, Tom Brunger, Axel T. Proc Natl Acad Sci U S A Biological Sciences Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein. National Academy of Sciences 2022-09-19 2022-10-04 /pmc/articles/PMC9546559/ /pubmed/36122200 http://dx.doi.org/10.1073/pnas.2210990119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Yang, Kailu
Wang, Chuchu
Kreutzberger, Alex J. B.
Ojha, Ravi
Kuivanen, Suvi
Couoh-Cardel, Sergio
Muratcioglu, Serena
Eisen, Timothy J.
White, K. Ian
Held, Richard G.
Subramanian, Subu
Marcus, Kendra
Pfuetzner, Richard A.
Esquivies, Luis
Doyle, Catherine A.
Kuriyan, John
Vapalahti, Olli
Balistreri, Giuseppe
Kirchhausen, Tom
Brunger, Axel T.
Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title_full Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title_fullStr Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title_full_unstemmed Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title_short Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
title_sort nanomolar inhibition of sars-cov-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546559/
https://www.ncbi.nlm.nih.gov/pubmed/36122200
http://dx.doi.org/10.1073/pnas.2210990119
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