An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike | Zendy

Michael Schoof | Zendy; Bryan Faust | Zendy; Reuben A. Saunders | Zendy; Smriti Sangwan | Zendy; Veronica V. Rezelj | Zendy; Nick Hoppe | Zendy; Morgane Boone | Zendy; Christian B. Billesbølle | Zendy; Cristina Puchades | Zendy; Caleigh M. Azumaya | Zendy; Huong T. Kratochvil | Zendy; Marcell Zimanyi | Zendy; Ishan Deshpande | Zendy; Jiahao Liang | Zendy; Sasha Dickinson | Zendy; Henry C. Nguyen | Zendy; Cynthia M. Chio | Zendy; Gregory E. Merz | Zendy; Michael C. Thompson | Zendy; Devan Diwanji | Zendy; Kaitlin Schaefer | Zendy; Aditya Anand | Zendy; Niv Dobzinski | Zendy; Beth Shoshana Zha | Zendy; Camille R. Simoneau | Zendy; Kristoffer E. Leon | Zendy; Kris M. White | Zendy; Un Seng Chio | Zendy; Meghna Gupta | Zendy; Mingliang Jin | Zendy; Fei Li | Zendy; Yanxin Liu | Zendy; Kaihua Zhang | Zendy; David Bulkley | Zendy; Ming Sun | Zendy; Amber M. Smith | Zendy; Alexandrea N. Rizo | Zendy; Frank R. Moss | Zendy; Axel F. Brilot | Zendy; Sergei Pourmal | Zendy; Raphael Trenker | Zendy; Thomas H. Pospiech | Zendy; Sayan Gupta | Zendy; Benjamin BarsiRhyne | Zendy; Vladislav Belyy | Zendy; Andrew W. Barile-Hill | Zendy; Silke Nock | Zendy; Yuwei Liu | Zendy; Nevan J. Krogan | Zendy; Corie Y. Ralston | Zendy; Danielle L. Swaney | Zendy; Adolfo Garcı́a-Sastre | Zendy; Mélanie Ott | Zendy; Marco Vignuzzi | Zendy; Peter Walter | Zendy; Aashish Manglik | Zendy; Julian R. Braxton | Zendy; Kyle E. Lopez | Zendy; Arthur A. Melo | Zendy; Joana Paulino | Zendy; Paul V. Thomas | Zendy; Feng Wang | Zendy; Zanlin Yu | Zendy; Miles Sasha Dickinson | Zendy; Daniel Asarnow | Zendy; Melody G. Campbell | Zendy; Junrui Li | Zendy; Tsz Kin Martin Tsui | Zendy; Donovan Trinidad | Zendy; Eric Tse | Zendy; Fengbo Zhou | Zendy; Nadia Herrera | Zendy; Ursula SchulzeGahmen | Zendy; I.D. Young | Zendy; J.T. Biel | Zendy; Xi Liu | Zendy; Carlos Nowotny | Zendy; Jianhua Zhao | Zendy; Alisa Bowen | Zendy; Yen-Li Li | Zendy; Phuong Nguyen | Zendy; Mali Safari | Zendy; Natalie Whitis | Zendy; Michelle Moritz | Zendy; Tristan W. Owens | Zendy; Amy Diallo | Zendy; Kate Kim | Zendy; Jessica K. Peters | Zendy; Erron W. Titus | Zendy; Jenny Chen | Zendy; Loan Doan | Zendy; Sebastián Flores | Zendy; Victor L. Lam | Zendy; Li Yang | Zendy; Megan Lo | Zendy; Aye C. Thwin | Zendy; Stephanie A. Wankowicz | Zendy; Sunny Zhang | Zendy; Arceli Joves | Zendy; Almarie Joves | Zendy; Liam McKay | Zendy; Mariano Tabios | Zendy; Oren S. Rosenberg | Zendy; Kliment A. Verba | Zendy; David A. Agard | Zendy; Yifan Cheng | Zendy; James S. Fraser | Zendy; Adam Frost | Zendy; Natalia Jura | Zendy; Tanja Kortemme | Zendy; Daniel R. Southworth | Zendy; Robert M. Stroud | Zendy

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An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Author(s) -

Michael Schoof,

Bryan Faust,

Reuben A. Saunders,

Smriti Sangwan,

Veronica V. Rezelj,

Nick Hoppe,

Morgane Boone,

Christian B. Billesbølle,

Cristina Puchades,

Caleigh M. Azumaya,

Huong T. Kratochvil,

Marcell Zimanyi,

Ishan Deshpande,

Jiahao Liang,

Sasha Dickinson,

Henry C. Nguyen,

Cynthia M. Chio,

Gregory E. Merz,

Michael C. Thompson,

Devan Diwanji,

Kaitlin Schaefer,

Aditya Anand,

Niv Dobzinski,

Beth Shoshana Zha,

Camille R. Simoneau,

Kristoffer E. Leon,

Kris M. White,

Un Seng Chio,

Meghna Gupta,

Mingliang Jin,

Fei Li,

Yanxin Liu,

Kaihua Zhang,

David Bulkley,

Ming Sun,

Amber M. Smith,

Alexandrea N. Rizo,

Frank R. Moss,

Axel F. Brilot,

Sergei Pourmal,

Raphael Trenker,

Thomas H. Pospiech,

Sayan Gupta,

Benjamin BarsiRhyne,

Vladislav Belyy,

Andrew W. Barile-Hill,

Silke Nock,

Yuwei Liu,

Nevan J. Krogan,

Corie Y. Ralston,

Danielle L. Swaney,

Adolfo Garcı́a-Sastre,

Mélanie Ott,

Marco Vignuzzi,

Peter Walter,

Aashish Manglik,

Julian R. Braxton,

Kyle E. Lopez,

Arthur A. Melo,

Joana Paulino,

Paul V. Thomas,

Feng Wang,

Zanlin Yu,

Miles Sasha Dickinson,

Daniel Asarnow,

Melody G. Campbell,

Junrui Li,

Tsz Kin Martin Tsui,

Donovan Trinidad,

Eric Tse,

Fengbo Zhou,

Nadia Herrera,

Ursula SchulzeGahmen,

I.D. Young,

J.T. Biel,

Xi Liu,

Carlos Nowotny,

Jianhua Zhao,

Alisa Bowen,

Yen-Li Li,

Phuong Nguyen,

Mali Safari,

Natalie Whitis,

Michelle Moritz,

Tristan W. Owens,

Amy Diallo,

Kate Kim,

Jessica K. Peters,

Erron W. Titus,

Jenny Chen,

Loan Doan,

Sebastián Flores,

Victor L. Lam,

Li Yang,

Megan Lo,

Aye C. Thwin,

Stephanie A. Wankowicz,

Sunny Zhang,

Arceli Joves,

Almarie Joves,

Liam McKay,

Mariano Tabios,

Oren S. Rosenberg,

Kliment A. Verba,

David A. Agard,

Yifan Cheng,

James S. Fraser,

Adam Frost,

Natalia Jura,

Tanja Kortemme,

Daniel R. Southworth,

Robert M. Stroud

Publication year - 2020

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.abe3255

Subject(s) - covid-19 , virology , spike protein , spike (software development) , sars virus , betacoronavirus , chemistry , biology , computer science , medicine , disease , pathology , infectious disease (medical specialty) , software engineering , outbreak

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

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