Nature Chemical Biology, volume 17, issue 1, pages 113-121
Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2
Colton J Bracken
1
,
Shion A. Lim
1
,
Paige Solomon
1
,
Nicholas J Rettko
1
,
P. Nguyen-Duy
1, 2
,
Beth Shoshana Zha
3
,
James R. Byrnes
1
,
Jie Zhou
1
,
Irene Lui
1
,
Jia Liu
1, 4
,
Katarina Pance
1
,
Axel F Brilot
1, 5, 6
,
Kyle E Lopez
,
Arthur Melo
,
Frank Moss
,
Alexandrea N Rizo
,
Ming Sun
,
Paul V. Thomas
,
Feng Wang
,
Julian R Braxton
,
Un Seng Chio
,
Miles Sasha Dickinson
,
Fei Li
,
Junrui Li
,
Yanxin Liu
,
Henry C Nguyen
,
Thomas H Pospiech
,
Donovan Trinidad
,
Kaihua Zhang
,
Christian Billesboelle
,
Alisa Bowen
,
Melody G Campbell
,
Devan Diwanji
,
Nick Hoppe
,
Yen-Li Li
,
Phuong Nguyen
,
Carlos Nowotny
,
Cristina Puchades
,
Mali Safari
,
Smriti Sangwan
,
Amber M. Smith
,
Raphael Trenker
,
Natalie Whitis
,
Jianhua Zhao
,
Daniel Asarnow
,
Caleigh M. Azumaya
,
Cynthia M. Chio
,
Bryan Faust
,
Kate Kim
,
Michelle Moritz
,
Tristan W Owens
,
Jessica K Peters
,
Sergei Pourmal
,
Kaitlin Schaefer
,
Tsz Kin Martin Tsui
,
Justin Biel
,
Ishan Deshpande
,
Nadia Herrera
,
Xi Liu
,
Ursula Schulze-Gahmen
,
Iris D. Young
,
Jen Chen
,
Amy Diallo
,
Loan Doan
,
Sebastian Flores
,
Meghna Gupta
,
Mingliang Jin
,
Huong T Kratochvil
,
Victor L Lam
,
Yang Li
,
Megan Lo
,
Gregory E Merz
,
Joana Paulino
,
Aye C Thwin
,
Erron W Titus
,
Zanlin Yu
,
Fengbo Zhou
,
Yang Zhang
,
David Bulkley
,
Arceli Joves
,
Almarie Joves
,
Liam Mckay
,
Mariano Tabios
,
Eric Tse
,
David A. Agard
,
Yifan Cheng
,
James S. Fraser
,
Adam Frost
,
Natalia Jura
,
Tanja Kortemme
,
Nevan J. Krogan
,
Aashish Manglik
,
Oren S Rosenberg
,
Daniel R Southworth
,
Robert M. Stroud
,
Kliment A. Verba
,
Xin X Zhou
,
Kevin K. Leung
,
James A. Wells
1
2
Lyell Immunopharma Inc., Seattle, USA
|
4
Merck & Co., South San Francisco, USA
|
6
Chan Zuckerberg BioHub, San Francisco, USA
|
Publication type: Journal Article
Publication date: 2020-10-20
Journal:
Nature Chemical Biology
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 14.8
ISSN: 15524450, 15524469
Molecular Biology
Cell Biology
Abstract
Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml−1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy. A screening approach finds VH-domain antibodies that bind the SARS-CoV-2 Spike protein receptor-binding domain at its interface with host ACE2. Bi-paratopic and multivalent binders have high affinity and potency.
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1 publication, 1.2%
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1 publication, 1.2%
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Hindawi Limited
1 publication, 1.2%
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eLife Sciences Publications
1 publication, 1.2%
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Proceedings of the National Academy of Sciences (PNAS)
1 publication, 1.2%
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Oxford University Press
1 publication, 1.2%
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1 publication, 1.2%
|
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Autonomous Non-profit Organization Editorial Board of the journal Uspekhi Khimii
1 publication, 1.2%
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2
4
6
8
10
12
14
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Bracken C. J. et al. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2 // Nature Chemical Biology. 2020. Vol. 17. No. 1. pp. 113-121.
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Bracken C. J. et al. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2 // Nature Chemical Biology. 2020. Vol. 17. No. 1. pp. 113-121.
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TY - JOUR
DO - 10.1038/s41589-020-00679-1
UR - https://doi.org/10.1038/s41589-020-00679-1
TI - Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2
T2 - Nature Chemical Biology
AU - Bracken, Colton J
AU - Lim, Shion A.
AU - Solomon, Paige
AU - Rettko, Nicholas J
AU - Nguyen-Duy, P.
AU - Zha, Beth Shoshana
AU - Schaefer, Kaitlin
AU - Byrnes, James R.
AU - Zhou, Jie
AU - Lui, Irene
AU - Liu, Jia
AU - Pance, Katarina
AU - Azumaya, Caleigh M.
AU - Braxton, Julian R
AU - Brilot, Axel F
AU - Gupta, Meghna
AU - Li, Fei
AU - Lopez, Kyle E
AU - Melo, Arthur
AU - Merz, Gregory E
AU - Moss, Frank
AU - Paulino, Joana
AU - Pospiech, Thomas H
AU - Pourmal, Sergei
AU - Puchades, Cristina
AU - Rizo, Alexandrea N
AU - Smith, Amber M.
AU - Sun, Ming
AU - Thomas, Paul V.
AU - Wang, Feng
AU - Yu, Zanlin
AU - Asarnow, Daniel
AU - Campbell, Melody G
AU - Chio, Cynthia M.
AU - Chio, Un Seng
AU - Dickinson, Miles Sasha
AU - Diwanji, Devan
AU - Faust, Bryan
AU - Hoppe, Nick
AU - Jin, Mingliang
AU - Li, Junrui
AU - Liu, Yanxin
AU - Nguyen, Henry C
AU - Sangwan, Smriti
AU - Trenker, Raphael
AU - Trinidad, Donovan
AU - Tse, Eric
AU - Zhang, Kaihua
AU - Zhou, Fengbo
AU - Billesboelle, Christian
AU - Bowen, Alisa
AU - Li, Yen-Li
AU - Nguyen, Phuong
AU - Nowotny, Carlos
AU - Safari, Mali
AU - Tsui, Tsz Kin Martin
AU - Whitis, Natalie
AU - Zhao, Jianhua
AU - Kim, Kate
AU - Moritz, Michelle
AU - Owens, Tristan W
AU - Peters, Jessica K
AU - Biel, Justin
AU - Deshpande, Ishan
AU - Herrera, Nadia
AU - Kratochvil, Huong T
AU - Liu, Xi
AU - Schulze-Gahmen, Ursula
AU - Young, Iris D.
AU - Chen, Jen
AU - Diallo, Amy
AU - Doan, Loan
AU - Flores, Sebastian
AU - Lam, Victor L
AU - Li, Yang
AU - Lo, Megan
AU - Thwin, Aye C
AU - Titus, Erron W
AU - Zhang, Yang
AU - Bulkley, David
AU - Joves, Arceli
AU - Joves, Almarie
AU - Mckay, Liam
AU - Tabios, Mariano
AU - Agard, David A.
AU - Cheng, Yifan
AU - Fraser, James S.
AU - Frost, Adam
AU - Jura, Natalia
AU - Kortemme, Tanja
AU - Krogan, Nevan J.
AU - Manglik, Aashish
AU - Rosenberg, Oren S
AU - Southworth, Daniel R
AU - Stroud, Robert M.
AU - Verba, Kliment A.
AU - Zhou, Xin X
AU - Leung, Kevin K.
AU - Wells, James A.
PY - 2020
DA - 2020/10/20 00:00:00
PB - Springer Nature
SP - 113-121
IS - 1
VL - 17
SN - 1552-4450
SN - 1552-4469
ER -
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@article{2020_Bracken,
author = {Colton J Bracken and Shion A. Lim and Paige Solomon and Nicholas J Rettko and P. Nguyen-Duy and Beth Shoshana Zha and Kaitlin Schaefer and James R. Byrnes and Jie Zhou and Irene Lui and Jia Liu and Katarina Pance and Caleigh M. Azumaya and Julian R Braxton and Axel F Brilot and Meghna Gupta and Fei Li and Kyle E Lopez and Arthur Melo and Gregory E Merz and Frank Moss and Joana Paulino and Thomas H Pospiech and Sergei Pourmal and Cristina Puchades and Alexandrea N Rizo and Amber M. Smith and Ming Sun and Paul V. Thomas and Feng Wang and Zanlin Yu and Daniel Asarnow and Melody G Campbell and Cynthia M. Chio and Un Seng Chio and Miles Sasha Dickinson and Devan Diwanji and Bryan Faust and Nick Hoppe and Mingliang Jin and Junrui Li and Yanxin Liu and Henry C Nguyen and Smriti Sangwan and Raphael Trenker and Donovan Trinidad and Eric Tse and Kaihua Zhang and Fengbo Zhou and Christian Billesboelle and Alisa Bowen and Yen-Li Li and Phuong Nguyen and Carlos Nowotny and Mali Safari and Tsz Kin Martin Tsui and Natalie Whitis and Jianhua Zhao and Kate Kim and Michelle Moritz and Tristan W Owens and Jessica K Peters and Justin Biel and Ishan Deshpande and Nadia Herrera and Huong T Kratochvil and Xi Liu and Ursula Schulze-Gahmen and Iris D. Young and Jen Chen and Amy Diallo and Loan Doan and Sebastian Flores and Victor L Lam and Yang Li and Megan Lo and Aye C Thwin and Erron W Titus and Yang Zhang and David Bulkley and Arceli Joves and Almarie Joves and Liam Mckay and Mariano Tabios and David A. Agard and Yifan Cheng and James S. Fraser and Adam Frost and Natalia Jura and Tanja Kortemme and Nevan J. Krogan and Aashish Manglik and Oren S Rosenberg and Daniel R Southworth and Robert M. Stroud and Kliment A. Verba and Xin X Zhou and Kevin K. Leung and James A. Wells},
title = {Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2},
journal = {Nature Chemical Biology},
year = {2020},
volume = {17},
publisher = {Springer Nature},
month = {oct},
url = {https://doi.org/10.1038/s41589-020-00679-1},
number = {1},
pages = {113--121},
doi = {10.1038/s41589-020-00679-1}
}
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Bracken, Colton J., et al. “Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.” Nature Chemical Biology, vol. 17, no. 1, Oct. 2020, pp. 113-121. https://doi.org/10.1038/s41589-020-00679-1.