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

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 nanobo...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Reports
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857409/
https://www.ncbi.nlm.nih.gov/pubmed/33154106
http://dx.doi.org/10.1126/science.abe3255
Descripción
Sumario: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.

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