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Multivalent designed proteins protect against SARS-CoV-2 variants of concern

Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to...

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Autores principales: Hunt, Andrew C., Case, James Brett, Park, Young-Jun, Cao, Longxing, Wu, Kejia, Walls, Alexandra C., Liu, Zhuoming, Bowen, John E., Yeh, Hsien-Wei, Saini, Shally, Helms, Louisa, Zhao, Yan Ting, Hsiang, Tien-Ying, Starr, Tyler N., Goreshnik, Inna, Kozodoy, Lisa, Carter, Lauren, Ravichandran, Rashmi, Green, Lydia B., Matochko, Wadim L., Thomson, Christy A., Vögeli, Bastain, Krüger-Gericke, Antje, VanBlargan, Laura A., Chen, Rita E., Ying, Baoling, Bailey, Adam L., Kafai, Natasha M., Boyken, Scott, Ljubetič, Ajasja, Edman, Natasha, Ueda, George, Chow, Cameron, Addetia, Amin, Panpradist, Nuttada, Gale, Michael, Freedman, Benjamin S., Lutz, Barry R., Bloom, Jesse D., Ruohola-Baker, Hannele, Whelan, Sean P. J., Stewart, Lance, Diamond, Michael S., Veesler, David, Jewett, Michael C., Baker, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282097/
https://www.ncbi.nlm.nih.gov/pubmed/34268509
http://dx.doi.org/10.1101/2021.07.07.451375
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author Hunt, Andrew C.
Case, James Brett
Park, Young-Jun
Cao, Longxing
Wu, Kejia
Walls, Alexandra C.
Liu, Zhuoming
Bowen, John E.
Yeh, Hsien-Wei
Saini, Shally
Helms, Louisa
Zhao, Yan Ting
Hsiang, Tien-Ying
Starr, Tyler N.
Goreshnik, Inna
Kozodoy, Lisa
Carter, Lauren
Ravichandran, Rashmi
Green, Lydia B.
Matochko, Wadim L.
Thomson, Christy A.
Vögeli, Bastain
Krüger-Gericke, Antje
VanBlargan, Laura A.
Chen, Rita E.
Ying, Baoling
Bailey, Adam L.
Kafai, Natasha M.
Boyken, Scott
Ljubetič, Ajasja
Edman, Natasha
Ueda, George
Chow, Cameron
Addetia, Amin
Panpradist, Nuttada
Gale, Michael
Freedman, Benjamin S.
Lutz, Barry R.
Bloom, Jesse D.
Ruohola-Baker, Hannele
Whelan, Sean P. J.
Stewart, Lance
Diamond, Michael S.
Veesler, David
Jewett, Michael C.
Baker, David
author_facet Hunt, Andrew C.
Case, James Brett
Park, Young-Jun
Cao, Longxing
Wu, Kejia
Walls, Alexandra C.
Liu, Zhuoming
Bowen, John E.
Yeh, Hsien-Wei
Saini, Shally
Helms, Louisa
Zhao, Yan Ting
Hsiang, Tien-Ying
Starr, Tyler N.
Goreshnik, Inna
Kozodoy, Lisa
Carter, Lauren
Ravichandran, Rashmi
Green, Lydia B.
Matochko, Wadim L.
Thomson, Christy A.
Vögeli, Bastain
Krüger-Gericke, Antje
VanBlargan, Laura A.
Chen, Rita E.
Ying, Baoling
Bailey, Adam L.
Kafai, Natasha M.
Boyken, Scott
Ljubetič, Ajasja
Edman, Natasha
Ueda, George
Chow, Cameron
Addetia, Amin
Panpradist, Nuttada
Gale, Michael
Freedman, Benjamin S.
Lutz, Barry R.
Bloom, Jesse D.
Ruohola-Baker, Hannele
Whelan, Sean P. J.
Stewart, Lance
Diamond, Michael S.
Veesler, David
Jewett, Michael C.
Baker, David
author_sort Hunt, Andrew C.
collection PubMed
description Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC(50) values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness.
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spelling pubmed-82820972021-07-16 Multivalent designed proteins protect against SARS-CoV-2 variants of concern Hunt, Andrew C. Case, James Brett Park, Young-Jun Cao, Longxing Wu, Kejia Walls, Alexandra C. Liu, Zhuoming Bowen, John E. Yeh, Hsien-Wei Saini, Shally Helms, Louisa Zhao, Yan Ting Hsiang, Tien-Ying Starr, Tyler N. Goreshnik, Inna Kozodoy, Lisa Carter, Lauren Ravichandran, Rashmi Green, Lydia B. Matochko, Wadim L. Thomson, Christy A. Vögeli, Bastain Krüger-Gericke, Antje VanBlargan, Laura A. Chen, Rita E. Ying, Baoling Bailey, Adam L. Kafai, Natasha M. Boyken, Scott Ljubetič, Ajasja Edman, Natasha Ueda, George Chow, Cameron Addetia, Amin Panpradist, Nuttada Gale, Michael Freedman, Benjamin S. Lutz, Barry R. Bloom, Jesse D. Ruohola-Baker, Hannele Whelan, Sean P. J. Stewart, Lance Diamond, Michael S. Veesler, David Jewett, Michael C. Baker, David bioRxiv Article Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC(50) values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness. Cold Spring Harbor Laboratory 2021-07-07 /pmc/articles/PMC8282097/ /pubmed/34268509 http://dx.doi.org/10.1101/2021.07.07.451375 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Hunt, Andrew C.
Case, James Brett
Park, Young-Jun
Cao, Longxing
Wu, Kejia
Walls, Alexandra C.
Liu, Zhuoming
Bowen, John E.
Yeh, Hsien-Wei
Saini, Shally
Helms, Louisa
Zhao, Yan Ting
Hsiang, Tien-Ying
Starr, Tyler N.
Goreshnik, Inna
Kozodoy, Lisa
Carter, Lauren
Ravichandran, Rashmi
Green, Lydia B.
Matochko, Wadim L.
Thomson, Christy A.
Vögeli, Bastain
Krüger-Gericke, Antje
VanBlargan, Laura A.
Chen, Rita E.
Ying, Baoling
Bailey, Adam L.
Kafai, Natasha M.
Boyken, Scott
Ljubetič, Ajasja
Edman, Natasha
Ueda, George
Chow, Cameron
Addetia, Amin
Panpradist, Nuttada
Gale, Michael
Freedman, Benjamin S.
Lutz, Barry R.
Bloom, Jesse D.
Ruohola-Baker, Hannele
Whelan, Sean P. J.
Stewart, Lance
Diamond, Michael S.
Veesler, David
Jewett, Michael C.
Baker, David
Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title_full Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title_fullStr Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title_full_unstemmed Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title_short Multivalent designed proteins protect against SARS-CoV-2 variants of concern
title_sort multivalent designed proteins protect against sars-cov-2 variants of concern
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282097/
https://www.ncbi.nlm.nih.gov/pubmed/34268509
http://dx.doi.org/10.1101/2021.07.07.451375
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