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

Science2020Vol. 370(6523), pp. 1473–1479

Citations Over TimeTop 10% of 2020 papers

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 Barsi‐Rhyne, 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, Caleigh M. Azumaya, Cristina Puchades, Ming Sun, 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, Alexandrea N. Rizo, Amber M. Smith, Paul V. Thomas, Feng Wang, Zanlin Yu, Miles Sasha Dickinson, Henry C. Nguyen, Daniel Asarnow, Melody G. Campbell, Cynthia M. Chio, Un Seng Chio, Devan Diwanji, Bryan Faust, Meghna Gupta, Nick Hoppe, Mingliang Jin, Junrui Li, Yanxin Liu, Gregory E. Merz, Smriti Sangwan, Tsz Kin Martin Tsui, Raphael Trenker, Donovan Trinidad, Eric Tse, Kaihua Zhang, Fengbo Zhou, Nadia Herrera, Huong T. Kratochvil, Ursula Schulze‐Gahmen, Michael C. Thompson, I.D. Young, J.T. Biel, Ishan Deshpande, Xi Liu, Christian B. Billesbølle, Carlos Nowotny, Amber M. Smith, Jianhua Zhao, Alisa Bowen, Nick Hoppe, Yen-Li Li, Phuong Nguyen, Mali Safari, Kaitlin Schaefer, 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, David Bulkley, 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, Nevan J. Krogan, Aashish Manglik, Daniel R. Southworth, Robert M. Stroud

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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Abstract

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