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Science
. 2020 Nov 5;eabe3255.
doi: 10.1126/science.abe3255. Online ahead of print.
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Michael Schoof # 1 2 , Bryan Faust # 3 2 4 5 , Reuben A Saunders # 3 6 , Smriti Sangwan # 3 2 , Veronica Rezelj # 7 , Nick Hoppe 4 5 , Morgane Boone 3 2 , Christian B Billesb?lle 4 5 , Cristina Puchades 5 , Caleigh M Azumaya 5 , Huong T Kratochvil 5 , Marcell Zimanyi 3 2 , Ishan Deshpande 4 5 , Jiahao Liang 4 , Sasha Dickinson 5 , Henry C Nguyen 5 , Cynthia M Chio 5 , Gregory E Merz 5 , Michael C Thompson 5 , Devan Diwanji 5 , Kaitlin Schaefer 5 , Aditya A Anand 3 2 , Niv Dobzinski 3 2 , Beth Shoshana Zha 8 , Camille R Simoneau 9 10 11 , Kristoffer Leon 9 10 11 , Kris M White 12 13 , Un Seng Chio 5 , Meghna Gupta 5 , Mingliang Jin 5 , Fei Li 5 , Yanxin Liu 5 , Kaihua Zhang 5 , David Bulkley 5 , Ming Sun 5 , Amber M Smith 5 , Alexandrea N Rizo 5 , Frank Moss 5 , Axel F Brilot 5 , Sergei Pourmal 5 , Raphael Trenker 5 , Thomas Pospiech 5 , Sayan Gupta 14 , Benjamin Barsi-Rhyne 4 , Vladislav Belyy 3 2 , Andrew W Barile-Hill 15 , Silke Nock 3 2 , Yuwei Liu 3 2 , Nevan J Krogan 5 6 9 10 , Corie Y Ralston 14 , Danielle L Swaney 5 6 9 10 , Adolfo Garc?a-Sastre 12 13 16 17 , Melanie Ott 9 10 11 , Marco Vignuzzi 7 , QCRG Structural Biology Consortium; Peter Walter 1 2 , Aashish Manglik 18 5 9 19
Collaborators, Affiliations
- PMID: 33154106
- DOI: 10.1126/science.abe3255
Abstract
The 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. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) 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.