Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784805067566612480 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9546559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yangkailu nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT wangchuchu nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT kreutzbergeralexjb nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT ojharavi nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT kuivanensuvi nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT couohcardelsergio nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT muratciogluserena nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT eisentimothyj nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT whitekian nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT heldrichardg nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT subramaniansubu nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT marcuskendra nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT pfuetznerricharda nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT esquiviesluis nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT doylecatherinea nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT kuriyanjohn nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT vapalahtiolli nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT balistrerigiuseppe nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT kirchhausentom nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein AT brungeraxelt nanomolarinhibitionofsarscov2infectionbyanunmodifiedpeptidetargetingtheprehairpinintermediateofthespikeprotein |