Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2 Article Swipe

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Colton J. Bracken , Shion A. Lim , Paige Solomon , Nicholas J. Rettko , Duy Nguyen , Beth Shoshana Zha , Kaitlin Schaefer , James R. Byrnes , Jie Zhou , Irene Lui , Jia Liu , Katarina Pance , Caleigh M. Azumaya , Julian R. Braxton , Axel F. Brilot , Meghna Gupta , Fei Li , Kyle E. Lopez , Arthur A. Melo , Gregory E. Merz , Frank R. Moss , Joana Paulino , Thomas H. Pospiech , Sergei Pourmal , Cristina Puchades , Alexandrea N. Rizo , Amber M. Smith , Ming Sun , Paul V. Thomas , Feng Wang , Zanlin Yu , Daniel Asarnow , Julian R. Braxton , Melody G. Campbell , Cynthia M. Chio , Un Seng Chio , Miles Sasha Dickinson , Devan Diwanji , Bryan Faust , Meghna Gupta , Nick Hoppe , Mingliang Jin , Fei Li , Junrui Li , Yanxin Liu , Gregory E. Merz , Henry C. Nguyen , Joana Paulino , Thomas H. Pospiech , Sergei Pourmal , Smriti Sangwan , Raphael Trenker , Donovan Trinidad , Eric Tse , Kaihua Zhang , Fengbo Zhou , Caleigh M. Azumaya , Christian Billesboelle , Alisa Bowen , Melody G. Campbell , Devan Diwanji , Nick Hoppe , Yen-Li Li , Phuong Nguyen , Carlos Nowotny , Cristina Puchades , Mali Safari , Smriti Sangwan , Kaitlin Schaefer , Amber M. Smith , Raphael Trenker , Tsz Kin Martin Tsui , Natalie Whitis , Jianhua Zhao , Daniel Asarnow , Caleigh M. Azumaya , Cynthia M. Chio , Bryan Faust , Meghna Gupta , Kate Kim , Michelle Moritz , Tristan W. Owens , Joana Paulino , Jessica K. Peters , Sergei Pourmal , Kaitlin Schaefer , Tsz Kin Martin Tsui , J.T. Biel , Ishan Deshpande , Nadia Herrera , Huong T. Kratochvil , Xi Liu , Ursula Schulze‐Gahmen , I.D. Young , Jen Chen , Amy Diallo , Loan Doan , Sebastián Flores , Meghna Gupta , Mingliang Jin ·

YOU? · · 2020 · Open Access · · DOI: https://doi.org/10.1038/s41589-020-00679-1

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.

Related Topics

Neutralization (Chemistry)

Phage Display

Chemistry

Potency (Pharmacology)

Infectious Diseases (Medical Specialty)

Histopathology

Disease

Concepts

Neutralization Epitope Phage display Chemistry Antibody Potency Binding site Spike Protein Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Peptide library Plasma protein binding Receptor Neutralizing antibody IC50 Coronavirus disease 2019 (COVID-19) Molecular biology Virus Virology Peptide Peptide sequence Biochemistry In vitro Biology Gene Genetics Medicine Infectious disease (medical specialty) Pathology Disease

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Type: article
Language: en
Landing Page: https://doi.org/10.1038/s41589-020-00679-1
PDF: https://www.nature.com/articles/s41589-020-00679-1.pdf
OA Status: bronze
Cited By: 107
References: 59
Related Works: 10
OpenAlex ID: https://openalex.org/W3094211096

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OpenAlex ID: https://openalex.org/W3094211096

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DOI: https://doi.org/10.1038/s41589-020-00679-1

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Title: Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2

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Type: article

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Language: en

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Publication year: 2020

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Publication date: 2020-10-20

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Authors: Colton J. Bracken, Shion A. Lim, Paige Solomon, Nicholas J. Rettko, Duy Nguyen, Beth Shoshana Zha, Kaitlin Schaefer, James R. Byrnes, Jie Zhou, Irene Lui, Jia Liu, Katarina Pance, Caleigh M. Azumaya, Julian R. Braxton, Axel F. Brilot, Meghna Gupta, Fei Li, Kyle E. Lopez, Arthur A. Melo, Gregory E. Merz, Frank R. Moss, Joana Paulino, Thomas H. Pospiech, Sergei Pourmal, Cristina Puchades, Alexandrea N. Rizo, Amber M. Smith, Ming Sun, Paul V. Thomas, Feng Wang, Zanlin Yu, Daniel Asarnow, Julian R. Braxton, Melody G. Campbell, Cynthia M. Chio, Un Seng Chio, Miles Sasha Dickinson, Devan Diwanji, Bryan Faust, Meghna Gupta, Nick Hoppe, Mingliang Jin, Fei Li, Junrui Li, Yanxin Liu, Gregory E. Merz, Henry C. Nguyen, Joana Paulino, Thomas H. Pospiech, Sergei Pourmal, Smriti Sangwan, Raphael Trenker, Donovan Trinidad, Eric Tse, Kaihua Zhang, Fengbo Zhou, Caleigh M. Azumaya, Christian Billesboelle, Alisa Bowen, Melody G. Campbell, Devan Diwanji, Nick Hoppe, Yen-Li Li, Phuong Nguyen, Carlos Nowotny, Cristina Puchades, Mali Safari, Smriti Sangwan, Kaitlin Schaefer, Amber M. Smith, Raphael Trenker, Tsz Kin Martin Tsui, Natalie Whitis, Jianhua Zhao, Daniel Asarnow, Caleigh M. Azumaya, Cynthia M. Chio, Bryan Faust, Meghna Gupta, Kate Kim, Michelle Moritz, Tristan W. Owens, Joana Paulino, Jessica K. Peters, Sergei Pourmal, Kaitlin Schaefer, Tsz Kin Martin Tsui, J.T. Biel, Ishan Deshpande, Nadia Herrera, Huong T. Kratochvil, Xi Liu, Ursula Schulze‐Gahmen, I.D. Young, Jen Chen, Amy Diallo, Loan Doan, Sebastián Flores, Meghna Gupta, Mingliang Jin

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Landing page: https://doi.org/10.1038/s41589-020-00679-1

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PDF URL: https://www.nature.com/articles/s41589-020-00679-1.pdf

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Concepts: Neutralization, Epitope, Phage display, Chemistry, Antibody, Potency, Binding site, Spike Protein, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Peptide library, Plasma protein binding, Receptor, Neutralizing antibody, IC50, Coronavirus disease 2019 (COVID-19), Molecular biology, Virus, Virology, Peptide, Peptide sequence, Biochemistry, In vitro, Biology, Gene, Genetics, Medicine, Infectious disease (medical specialty), Pathology, Disease

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Cited by: 107

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Citations by year (recent): 2025: 8, 2024: 17, 2023: 9, 2022: 24, 2021: 45

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References (count): 59

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Related works (count): 10

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