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Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance
The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982573/ https://www.ncbi.nlm.nih.gov/pubmed/35253970 http://dx.doi.org/10.15252/embr.202154199 |
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author | Walter, Justin D Scherer, Melanie Hutter, Cedric A J Garaeva, Alisa A Zimmermann, Iwan Wyss, Marianne Rheinberger, Jan Ruedin, Yelena Earp, Jennifer C Egloff, Pascal Sorgenfrei, Michèle Hürlimann, Lea M Gonda, Imre Meier, Gianmarco Remm, Sille Thavarasah, Sujani van Geest, Geert Bruggmann, Rémy Zimmer, Gert Slotboom, Dirk J Paulino, Cristina Plattet, Philippe Seeger, Markus A |
author_facet | Walter, Justin D Scherer, Melanie Hutter, Cedric A J Garaeva, Alisa A Zimmermann, Iwan Wyss, Marianne Rheinberger, Jan Ruedin, Yelena Earp, Jennifer C Egloff, Pascal Sorgenfrei, Michèle Hürlimann, Lea M Gonda, Imre Meier, Gianmarco Remm, Sille Thavarasah, Sujani van Geest, Geert Bruggmann, Rémy Zimmer, Gert Slotboom, Dirk J Paulino, Cristina Plattet, Philippe Seeger, Markus A |
author_sort | Walter, Justin D |
collection | PubMed |
description | The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants. |
format | Online Article Text |
id | pubmed-8982573 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89825732022-04-15 Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance Walter, Justin D Scherer, Melanie Hutter, Cedric A J Garaeva, Alisa A Zimmermann, Iwan Wyss, Marianne Rheinberger, Jan Ruedin, Yelena Earp, Jennifer C Egloff, Pascal Sorgenfrei, Michèle Hürlimann, Lea M Gonda, Imre Meier, Gianmarco Remm, Sille Thavarasah, Sujani van Geest, Geert Bruggmann, Rémy Zimmer, Gert Slotboom, Dirk J Paulino, Cristina Plattet, Philippe Seeger, Markus A EMBO Rep Articles The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants. John Wiley and Sons Inc. 2022-03-07 /pmc/articles/PMC8982573/ /pubmed/35253970 http://dx.doi.org/10.15252/embr.202154199 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Walter, Justin D Scherer, Melanie Hutter, Cedric A J Garaeva, Alisa A Zimmermann, Iwan Wyss, Marianne Rheinberger, Jan Ruedin, Yelena Earp, Jennifer C Egloff, Pascal Sorgenfrei, Michèle Hürlimann, Lea M Gonda, Imre Meier, Gianmarco Remm, Sille Thavarasah, Sujani van Geest, Geert Bruggmann, Rémy Zimmer, Gert Slotboom, Dirk J Paulino, Cristina Plattet, Philippe Seeger, Markus A Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title | Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title_full | Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title_fullStr | Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title_full_unstemmed | Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title_short | Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance |
title_sort | biparatopic sybodies neutralize sars‐cov‐2 variants of concern and mitigate drug resistance |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982573/ https://www.ncbi.nlm.nih.gov/pubmed/35253970 http://dx.doi.org/10.15252/embr.202154199 |
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