An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Michael Schoof,Bryan Faust,R.A. Saunders,Smriti Sangwan,Veronica V. Rezelj,Nick Hoppe,Morgane Boone,Christian B. Billesbølle,Cristina Puchades,Caleigh M. Azumaya,Huong T. Kratochvil,M. Zimanyi,Ishan Deshpande,Jiahao Liang,S. Dickinson,Henry C. Nguyen,Cynthia M. Chio,Gregory E. Merz,Michael C. Thompson,Devan Diwanji,Kaitlin Schaefer,Aditya A. Anand,Niv Dobzinski,Beth S. Zha,Camille R. Simoneau,Camille R. Simoneau,Kristoffer E. Leon,Kristoffer E. Leon,Kris M. White,Un Seng Chio,Meghna Gupta,Mingliang Jin,Fei Li,Yanxin Liu,Kaihua Zhang,David Bulkley,Ming Sun,Amber M. Smith,Alexandrea N. Rizo,Frank R. Moss,Axel F. Brilot,Sergei Pourmal,Raphael Trenker,Thomas H. Pospiech,Sayan Gupta,Benjamin Barsi-Rhyne,Vladislav Belyy,A.W. Barile-Hill,Silke Nock,Yuwei Liu,Nevan J. Krogan,Corie Y. Ralston,Danielle L. Swaney,Adolfo García-Sastre,Melanie Ott,Melanie Ott,Marco Vignuzzi,Peter Walter,Aashish Manglik +58 more
TLDR
Nanobodies that bind tightly to spike and efficiently neutralize SARS-CoV-2 in cells are reported, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.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.read more
Citations
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Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting novel and conserved epitopes
Dapeng Sun,Zhe Sang,Yong Joon Kim,Yufei Xiang,Tomer Cohen,Anna K. Belford,Alexis Huet,James F. Conway,Ji Sun,Derek J. Taylor,Dina Schneidman-Duhovny,Cheng Zhang,Wei Huang,Yi Shi +13 more
TL;DR: In this paper, the authors found that potent neutralizing Nbs are highly resistant to the convergent variants of concern that evade a large panel of neutralizing antibodies (Abs) and significantly reduce the activities of convalescent or vaccine-elicited sera.
Journal ArticleDOI
Outlook of therapeutic and diagnostic competency of nanobodies against SARS-CoV-2: A systematic review
Hamid Aria,Fatemeh Mahmoodi,Hooria Seyedhosseini Ghaheh,Hamed Zare,Mohammad Heiat,Hamid Bakherad +5 more
TL;DR: In this article , the application of nanobodies in the treatment and detection of COVID-19 infection was reviewed, and the results showed that extensive and sufficient studies have been performed in the field of production of Nanobodies against SARS-CoV-2 virus.
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Multimeric nanobodies from camelid engineered mice and llamas potently neutralize SARS-CoV-2 variants
Jianliang Xu,Kai Xu,Seol Kyoung Jung,Andrea Conte,Jenna Ariel Lieberman,Frauke Muecksch,Julio C. C. Lorenzi,Solji Park,Zijun Wang,Lino Tessarollo,Tatsiana Bylund,Gwo-Yu Chuang,Adam S. Olia,I-Ting Teng,Tongqing Zhou,Tyler Stephens,Yaroslav Tsybovsky,Paul D. Bieniasz,Paul D. Bieniasz,Theodora Hatziioannou,Michel C. Nussenzweig,Michel C. Nussenzweig,Peter D. Kwong,Rafael Casellas +23 more
TL;DR: In this article, the authors demonstrate that multivalent nanobodies overcome SARS-CoV-2 variant mutations through two separate mechanisms: enhanced avidity for the ACE2 binding domain, and recognition of conserved epitopes largely inaccessible to human antibodies.
Journal ArticleDOI
Structural Insights into the Design of Synthetic Nanobody Libraries
TL;DR: Over a dozen synthetic nanobody libraries reported so far are reviewed and the different approaches followed in their construction and validation are discussed, with an emphasis on framework and hypervariable loop design as critical issues defining their potential as high-class nanobodies sources.
Journal ArticleDOI
Development of potent and effective synthetic SARS-CoV-2 neutralizing nanobodies.
Maxwell Stefan,Yooli Kim Light,Jennifer L. Schwedler,Peter R. McIlroy,Colleen M. Courtney,Edwin A. Saada,Christine E. Thatcher,Ashlee M. Phillips,Feliza Bourguet,Catherine M Mageeney,Summer A. McCloy,Nicole M. Collette,Oscar A. Negrete,Joseph S. Schoeniger,Dina R. Weilhammer,Brooke Harmon +15 more
TL;DR: In this article, neutralizing humanized nanobody-based antibodies (VHH-huFc) have been used to address the current SARS-CoV-2 pandemic and provide a powerful toolkit to address future virus outbreaks.
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