An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Michael Schoof(Howard Hughes Medical Institute), Bryan Faust(Howard Hughes Medical Institute), Reuben A. Saunders(Howard Hughes Medical Institute), Smriti Sangwan(Howard Hughes Medical Institute), Veronica V. Rezelj(Centre National de la Recherche Scientifique), Nick Hoppe(University of California, San Francisco), Morgane Boone(Howard Hughes Medical Institute), Christian B. Billesbølle(University of California, San Francisco), Cristina Puchades(Quantitative BioSciences), Caleigh M. Azumaya(Quantitative BioSciences), Huong T. Kratochvil(Quantitative BioSciences), Marcell Zimanyi(Howard Hughes Medical Institute), Ishan Deshpande(University of California, San Francisco), Jiahao Liang(University of California, San Francisco), Sasha Dickinson(Quantitative BioSciences), Henry C. Nguyen(Quantitative BioSciences), Cynthia M. Chio(Quantitative BioSciences), Gregory E. Merz(Quantitative BioSciences), Michael C. Thompson(Quantitative BioSciences), Devan Diwanji(Quantitative BioSciences), Kaitlin Schaefer(Quantitative BioSciences), Aditya Anand(Howard Hughes Medical Institute), Niv Dobzinski(Howard Hughes Medical Institute), Beth Shoshana Zha(University of California, San Francisco), Camille R. Simoneau(Gladstone Institutes), Kristoffer E. Leon(Gladstone Institutes), Kris M. White(Icahn School of Medicine at Mount Sinai), Un Seng Chio(Quantitative BioSciences), Meghna Gupta(Quantitative BioSciences), Mingliang Jin(Quantitative BioSciences), Fei Li(Quantitative BioSciences), Yanxin Liu(Howard Hughes Medical Institute), Kaihua Zhang(Quantitative BioSciences), David Bulkley(Quantitative BioSciences), Ming Sun(Quantitative BioSciences), Amber M. Smith(Quantitative BioSciences), Alexandrea N. Rizo(Quantitative BioSciences), Frank R. Moss(Quantitative BioSciences), Axel F. Brilot(Quantitative BioSciences), Sergei Pourmal(Quantitative BioSciences), Raphael Trenker(Quantitative BioSciences), Thomas H. Pospiech(Quantitative BioSciences), Sayan Gupta(Lawrence Berkeley National Laboratory), Benjamin Barsi‐Rhyne(University of California, San Francisco), Vladislav Belyy(Howard Hughes Medical Institute), Andrew W. Barile-Hill, Silke Nock(Howard Hughes Medical Institute), Yuwei Liu(Howard Hughes Medical Institute), Nevan J. Krogan(Gladstone Institutes), Corie Y. Ralston(Lawrence Berkeley National Laboratory), Danielle L. Swaney(Gladstone Institutes), Adolfo García‐Sastre(Icahn School of Medicine at Mount Sinai), Mélanie Ott(Gladstone Institutes), Marco Vignuzzi(Centre National de la Recherche Scientifique), Peter Walter(Howard Hughes Medical Institute), Aashish Manglik(University of California, San Francisco), Caleigh M. Azumaya(Quantitative BioSciences), Cristina Puchades(Quantitative BioSciences), Ming Sun(Quantitative BioSciences), Julian R. Braxton, Axel F. Brilot(Quantitative BioSciences), Meghna Gupta(Quantitative BioSciences), Fei Li(Quantitative BioSciences), Kyle E. Lopez, Arthur A. Melo, Gregory E. Merz(Quantitative BioSciences), Frank R. Moss(Quantitative BioSciences), Joana Paulino, Thomas H. Pospiech(Quantitative BioSciences), Sergei Pourmal(Quantitative BioSciences), Alexandrea N. Rizo(Quantitative BioSciences), Amber M. Smith(Quantitative BioSciences), Paul V. Thomas(Quantitative BioSciences), Feng Wang, Zanlin Yu(Howard Hughes Medical Institute), Miles Sasha Dickinson(Quantitative BioSciences), Henry C. Nguyen(Quantitative BioSciences), Daniel Asarnow(Gladstone Institutes), Melody G. Campbell, Cynthia M. Chio(Quantitative BioSciences), Un Seng Chio(Quantitative BioSciences), Devan Diwanji(Quantitative BioSciences), Bryan Faust(Howard Hughes Medical Institute), Meghna Gupta(Quantitative BioSciences), Nick Hoppe(University of California, San Francisco), Mingliang Jin(Quantitative BioSciences), Junrui Li(University of California, San Francisco), Yanxin Liu(Howard Hughes Medical Institute), Gregory E. Merz(Quantitative BioSciences), Smriti Sangwan(Howard Hughes Medical Institute), Tsz Kin Martin Tsui, Raphael Trenker(Quantitative BioSciences), Donovan Trinidad, Eric Tse, Kaihua Zhang(Quantitative BioSciences), Fengbo Zhou, Nadia Herrera, Huong T. Kratochvil(Quantitative BioSciences), Ursula Schulze‐Gahmen, Michael C. Thompson(Quantitative BioSciences), I.D. Young, J.T. Biel, Ishan Deshpande(University of California, San Francisco), Xi Liu(Quantitative BioSciences), Christian B. Billesbølle(University of California, San Francisco), Carlos Nowotny, Amber M. Smith(Quantitative BioSciences), Jianhua Zhao, Alisa Bowen, Nick Hoppe(University of California, San Francisco), Yen-Li Li(University of California, San Francisco), Phuong Nguyen(Quantitative BioSciences), Mali Safari, Kaitlin Schaefer(Quantitative BioSciences), 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(University of California, San Francisco), Megan Lo(Quantitative BioSciences), Aye C. Thwin, Stephanie A. Wankowicz, Sunny Zhang(Quantitative BioSciences), David Bulkley(Quantitative BioSciences), Arceli Joves, Almarie Joves, Liam McKay, Mariano Tabios, Oren S. Rosenberg, Kliment A. Verba, David A. Agard(Quantitative BioSciences), Yifan Cheng, James S. Fraser, Adam Frost, Natalia Jura, Tanja Kortemme, Nevan J. Krogan(Gladstone Institutes), Aashish Manglik(University of California, San Francisco), Daniel R. Southworth, Robert M. Stroud
Cited by 466Open Access
Abstract
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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