Science (New York, N.Y.) · 2020

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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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, QCRG Structural Biology Consortium, Walter Peter, Manglik Aashish

Аннотация

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.

Предметные рубрики MeSH

Angiotensin-Converting Enzyme 2 Animals Antibodies, Neutralizing Antibodies, Viral Antibody Affinity Chlorocebus aethiops Cryoelectron Microscopy Humans Neutralization Tests Protein Binding Protein Stability Single-Domain Antibodies Spike Glycoprotein, Coronavirus Vero Cells

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH