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
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A Small Virus to Deliver Small Antibodies: New Targeted Therapies Based on AAV Delivery of Nanobodies
TL;DR: In this paper, a review of the applications in which AAV vectors have been used to deliver nanobodies, with a focus on their therapeutic use, is presented, including cancer, neurological, cardiovascular, infectious, and genetic diseases.
Journal ArticleDOI
Implementing a method for engineering multivalency to substantially enhance binding of clinical trial anti-SARS-CoV-2 antibodies to wildtype spike and variants of concern proteins.
Adam Leach,Ami Miller,Emma M. Bentley,Giada Mattiuzzo,Jemima Thomas,Craig McAndrew,Rob L. M. van Montfort,Terence H. Rabbitts +7 more
TL;DR: In this paper, the authors applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies.
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XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants
Bernard Vanhove,Stéphane Marot,Ray T.Y. So,Benjamin Gaborit,Gwénaëlle Evanno,Isabelle Malet,Guillaume Lafrogne,Edwige Mevel,Carine Ciron,Pierre-Joseph Royer,Elsa Lheriteau,François Raffi,Roberto Bruzzone,Roberto Bruzzone,Chris Ka Pun Mok,Chris Ka Pun Mok,Chris Ka Pun Mok,Odile Duvaux,Anne-Geneviève Marcelin,Vincent Calvez +19 more
TL;DR: XAV-19 as mentioned in this paper is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2.
Posted ContentDOI
Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein
Zara Y. Weinberg,Claire E Hilburger,Matthew Sun-min Kim,Longxing Cao,Mir M. Khalid,Sarah Elmes,Devan Diwanji,Evelyn Hernandez,Jocelyne Lopez,Kaitlin Schaefer,Amber M. Smith,Fengbo Zhou,G. Renuka Kumar,Melanie Ott,David Baker,David Baker,Hana El-Samad +16 more
TL;DR: In this paper, a live cell sensor (SARSNotch) was developed using a de novo-designed protein binder against the SARS-CoV-2 Spike protein.
Posted ContentDOI
Accelerating PERx Reaction Enables Covalent Nanobodies for Potent Neutralization of SARS-Cov-2 and Variants
TL;DR: This work has developed covalent nanobodies capable of binding with SARS-CoV-2 spike protein irreversibly via proximity-enabled reactive therapeutic (PERx) mechanism and uncovered insights on potency increase that can be valuable to developing effective therapeutics for various viral infections.
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