| Literature DB >> 33154106 |
Michael Schoof1,2, Bryan Faust3,2,4,5, Reuben A Saunders3,6, Smriti Sangwan3,2, Veronica Rezelj7, Nick Hoppe4,5, Morgane Boone3,2, Christian B Billesbølle4,5, Cristina Puchades5, Caleigh M Azumaya5, Huong T Kratochvil5, Marcell Zimanyi3,2, Ishan Deshpande4,5, Jiahao Liang4, Sasha Dickinson5, Henry C Nguyen5, Cynthia M Chio5, Gregory E Merz5, Michael C Thompson5, Devan Diwanji5, Kaitlin Schaefer5, Aditya A Anand3,2, Niv Dobzinski3,2, Beth Shoshana Zha8, Camille R Simoneau9,10,11, Kristoffer Leon9,10,11, Kris M White12,13, Un Seng Chio5, Meghna Gupta5, Mingliang Jin5, Fei Li5, Yanxin Liu5, Kaihua Zhang5, David Bulkley5, Ming Sun5, Amber M Smith5, Alexandrea N Rizo5, Frank Moss5, Axel F Brilot5, Sergei Pourmal5, Raphael Trenker5, Thomas Pospiech5, Sayan Gupta14, Benjamin Barsi-Rhyne4, Vladislav Belyy3,2, Andrew W Barile-Hill15, Silke Nock3,2, Yuwei Liu3,2, Nevan J Krogan5,6,9,10, Corie Y Ralston14, Danielle L Swaney5,6,9,10, Adolfo García-Sastre12,13,16,17, Melanie Ott9,10,11, Marco Vignuzzi7, Peter Walter1,2, Aashish Manglik18,5,9,19.
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.Entities:
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Year: 2020 PMID： 33154106 PMCID： PMC7857409 DOI： 10.1126/science.abe3255
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 63.714