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Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor
The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068829/ https://www.ncbi.nlm.nih.gov/pubmed/36940324 http://dx.doi.org/10.1073/pnas.2300360120 |
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author | Yang, Kailu Wang, Chuchu Kreutzberger, Alex J. B. White, K. Ian Pfuetzner, Richard A. Esquivies, Luis Kirchhausen, Tomas Brunger, Axel T. |
author_facet | Yang, Kailu Wang, Chuchu Kreutzberger, Alex J. B. White, K. Ian Pfuetzner, Richard A. Esquivies, Luis Kirchhausen, Tomas Brunger, Axel T. |
author_sort | Yang, Kailu |
collection | PubMed |
description | The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that one of these mutations, N969K induces a substantial displacement in the structure of the heptad repeat 2 (HR2) backbone in the HR1HR2 postfusion bundle. Due to this mutation, fusion-entry peptide inhibitors based on the Wuhan strain sequence are less efficacious. Here, we report an Omicron-specific peptide inhibitor designed based on the structure of the Omicron HR1HR2 postfusion bundle. Specifically, we inserted an additional residue in HR2 near the Omicron HR1 K969 residue to better accommodate the N969K mutation and relieve the distortion in the structure of the HR1HR2 postfusion bundle it introduced. The designed inhibitor recovers the loss of inhibition activity of the original longHR2_42 peptide with the Wuhan strain sequence against the Omicron variant in both a cell–cell fusion assay and a vesicular stomatitis virus (VSV)-SARS-CoV-2 chimera infection assay, suggesting that a similar approach could be used to combat future variants. From a mechanistic perspective, our work suggests the interactions in the extended region of HR2 may mediate the initial landing of HR2 onto HR1 during the transition of the S protein from the prehairpin intermediate to the postfusion state. |
format | Online Article Text |
id | pubmed-10068829 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-100688292023-04-04 Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor Yang, Kailu Wang, Chuchu Kreutzberger, Alex J. B. White, K. Ian Pfuetzner, Richard A. Esquivies, Luis Kirchhausen, Tomas Brunger, Axel T. Proc Natl Acad Sci U S A Biological Sciences The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that one of these mutations, N969K induces a substantial displacement in the structure of the heptad repeat 2 (HR2) backbone in the HR1HR2 postfusion bundle. Due to this mutation, fusion-entry peptide inhibitors based on the Wuhan strain sequence are less efficacious. Here, we report an Omicron-specific peptide inhibitor designed based on the structure of the Omicron HR1HR2 postfusion bundle. Specifically, we inserted an additional residue in HR2 near the Omicron HR1 K969 residue to better accommodate the N969K mutation and relieve the distortion in the structure of the HR1HR2 postfusion bundle it introduced. The designed inhibitor recovers the loss of inhibition activity of the original longHR2_42 peptide with the Wuhan strain sequence against the Omicron variant in both a cell–cell fusion assay and a vesicular stomatitis virus (VSV)-SARS-CoV-2 chimera infection assay, suggesting that a similar approach could be used to combat future variants. From a mechanistic perspective, our work suggests the interactions in the extended region of HR2 may mediate the initial landing of HR2 onto HR1 during the transition of the S protein from the prehairpin intermediate to the postfusion state. National Academy of Sciences 2023-03-20 2023-03-28 /pmc/articles/PMC10068829/ /pubmed/36940324 http://dx.doi.org/10.1073/pnas.2300360120 Text en Copyright © 2023 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. White, K. Ian Pfuetzner, Richard A. Esquivies, Luis Kirchhausen, Tomas Brunger, Axel T. Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title | Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title_full | Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title_fullStr | Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title_full_unstemmed | Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title_short | Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor |
title_sort | structure-based design of a sars-cov-2 omicron-specific inhibitor |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068829/ https://www.ncbi.nlm.nih.gov/pubmed/36940324 http://dx.doi.org/10.1073/pnas.2300360120 |
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