학술논문
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Document Type
article
Author
Schoof, Michael; Faust, Bryan; Saunders, Reuben A; Sangwan, Smriti; Rezelj, Veronica; Hoppe, Nick; Boone, Morgane; Billesbølle, Christian B; Puchades, Cristina; Azumaya, Caleigh M; Kratochvil, Huong T; Zimanyi, Marcell; Deshpande, Ishan; Liang, Jiahao; Dickinson, Sasha; Nguyen, Henry C; Chio, Cynthia M; Merz, Gregory E; Thompson, Michael C; Diwanji, Devan; Schaefer, Kaitlin; Anand, Aditya A; Dobzinski, Niv; Zha, Beth Shoshana; Simoneau, Camille R; Leon, Kristoffer; White, Kris M; Chio, Un Seng; Gupta, Meghna; Jin, Mingliang; Li, Fei; Liu, Yanxin; Zhang, Kaihua; Bulkley, David; Sun, Ming; Smith, Amber M; Rizo, Alexandrea N; Moss, Frank; Brilot, Axel F; Pourmal, Sergei; Trenker, Raphael; Pospiech, Thomas; Gupta, Sayan; Barsi-Rhyne, Benjamin; Belyy, Vladislav; Barile-Hill, Andrew W; Nock, Silke; Liu, Yuwei; Krogan, Nevan J; Ralston, Corie Y; Swaney, Danielle L; García-Sastre, Adolfo; Ott, Melanie; Vignuzzi, Marco; Walter, Peter; Manglik, Aashish; Braxton, Julian R; Lopez, Kyle E; Melo, Arthur; Paulino, Joana; Pospiech, Thomas H; Thomas, Paul V; Wang, Feng; Yu, Zanlin; Dickinson, Miles Sasha; Asarnow, Daniel; Campbell, Melody G; Li, Junrui; Tsui, Tsz Kin Martin; Trinidad, Donovan; Tse, Eric; Zhou, Fengbo; Herrera, Nadia; Schulze-Gahmen, Ursula
Source
Science. 370(6523)
Subject
Language
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.