• Michael Schoof, Bryan Faust, Reuben A Saunders, Smriti Sangwan, Veronica 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 A Anand, Niv Dobzinski, Beth Shoshana Zha, Camille R Simoneau, Kristoffer 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 Moss, Axel F Brilot, Sergei Pourmal, Raphael Trenker, Thomas 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 García-Sastre, Melanie Ott, Marco Vignuzzi, QCRG Structural Biology Consortium, Peter Walter, and Aashish Manglik.
• Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA. michael@walterlab.ucsf.edu peter@walterlab.ucsf.edu aashish.manglik@ucsf.edu.
• Science. 2020 Dec 18; 370 (6523): 1473-1479.

AbstractThe 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.Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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