作者: Dickinson, Sasha ; Frost, Adam ; Thwin, Aye C. ; McKay, Liam ; Southworth, Daniel R. ; Dobzinski, Niv ; Sangwan, Smriti ; Dickinson, Miles Sasha ; Whitis, Natalie ; Chen, Jenny ; Wankowicz, Stephanie ; Belyy, Vladislav ; Campbell, Melody G. ; Anand, Aditya A. ; Nguyen, Henry C. ; Li, Fei ; Swaney, Danielle L. ; Chio, Cynthia M. ; Boone, Morgane ; Li, Yang ; Tse, Eric ; Moritz, Michelle ; Verba, Kliment A. ; Zhao, Jianhua ; Schulze-Gahmen, Ursula ; Deshpande, Ishan ; Tsui, Tsz Kin Martin ; Lopez, Kyle E. ; Smith, Amber M. ; Ott, Melanie ; Trinidad, Donovan ; Doan, Loan ; Azumaya, Caleigh M. ; Brilot, Axel F. ; Manglik, Aashish ; Puchades, Cristina ; Chio, Un Seng ; Lam, Victor L. ; Bulkley, David ; García-Sastre, Adolfo ; Diwanji, Devan ; Liu, Yuwei ; Stroud, Robert M. ; Schaefer, Kaitlin ; Thomas, Paul V. ; Jin, Mingliang ; Kratochvil, Huong T. ; Zhou, Fengbo ; Barile-Hill, Andrew W. ; Ralston, Corie Y. ; Trenker, Raphael ; Nowotny, Carlos ; Rezelj, Veronica ; Joves, Arceli ; Tabios, Mariano ; Owens, Tristan W. ; Faust, Bryan ; Peters, Jessica K. ; Agard, David A. ; Walter, Peter ; Lo, Megan ; Simoneau, Camille R. ; Merz, Gregory E. ; Braxton, Julian R. ; Jura, Natalia ; Zha, Beth Shoshana ; Moss, Frank ; Cheng, Yifan ; Paulino, Joana ; Diallo, Amy ; Asarnow, Daniel ; Leon, Kristoffer ; Liang, Jiahao ; Pourmal, Sergei ; Rosenberg, Oren S. ; Billesbølle, Christian Bache ; Liu, Xi ; Gupta, Meghna ; Vignuzzi, Marco ; Kortemme, Tanja ; Billesbølle, Christian B. ; Kim, Kate ; Young, Iris D. ; Melo, Arthur ; Rizo, Alexandrea N. ; Liu, Yanxin ; Zhang, Yang ; Nock, Silke ; Wang, Feng ; Titus, Erron W. ; Barsi-Rhyne, Benjamin ; Joves, Almarie ; Safari, Mali ; Gupta, Sayan ; Pospiech, Thomas ; Krogan, Nevan J. ; Thompson, Michael C. ; White, Kris M. ; Herrera, Nadia ; Zhang, Kaihua ; Biel, Justin ; Bowen, Alisa ; Nguyen, Phuong ; Yu, Zanlin ; Fraser, James S. ; Saunders, Reuben A. ; Flores, Sebastian ; Thompson, Michael C. ; Hoppe, Nick ; Schoof, Michael ; Sun, Ming ; Zimanyi, Marcell ; Pospiech, Thomas H. ; Li, Junrui ; Li, Yen-Li

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.

An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation

作者: Deshpande, Ishan ; Dickinson, Sasha ; Swaney, Danielle L ; Faust, Bryan ; Chio, Cynthia M ; Liu, Yanxin ; Nock, Silke ; Ott, Melanie ; Dobzinski, Niv ; Sangwan, Smriti ; Walter, Peter ; Merz, Gregory E ; Rizo, Alexandrea N ; Barsi-Rhyne, Benjamin ; Belyy, Vladislav ; Azumaya, Caleigh M ; Thompson, Michael C ; Billesbølle, Christian B ; Moss, Frank ; Zha, Beth Shoshana ; Gupta, Sayan ; Manglik, Aashish ; Barile-Hill, Andrew W ; Pospiech, Thomas ; Saunders, Reuben A ; Krogan, Nevan J ; Kratochvil, Huong T ; Puchades, Cristina ; Smith, Amber M ; Brilot, Axel F ; White, Kris M ; Chio, Un Seng ; Ralston, Corie Y ; Leon, Kristoffer ; Nguyen, Henry C ; Zhang, Kaihua ; García-Sastre, Adolfo ; Li, Fei ; Bulkley, David ; Liang, Jiahao ; Diwanji, Devan ; Liu, Yuwei ; Simoneau, Camille R ; Boone, Morgane ; Pourmal, Sergei ; Schaefer, Kaitlin ; Jin, Mingliang ; Hoppe, Nick ; Gupta, Meghna ; Schoof, Michael ; Trenker, Raphael ; Vignuzzi, Marco ; Rezelj, Veronica ; Sun, Ming ; Zimanyi, Marcell ; Anand, Aditya A

ABSTRACTWithout an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable 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 SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

100 项与 Nanobody(Cytiva Life Sciences) 相关的药物交易

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