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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Journal ArticleDOI
Mechanisms of SARS-CoV-2 entry into cells.
TL;DR: In this article, structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the spike (S) protein with ACE2, engagement of the receptor-binding domain of the S protein with ACS, proteolytic activation of S protein, endocytosis and membrane fusion are provided.
Journal ArticleDOI
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.
Constantinos Kurt Wibmer,Frances Ayres,Tandile Hermanus,Mashudu Madzivhandila,Prudence Kgagudi,Brent Oosthuysen,Bronwen E. Lambson,Bronwen E. Lambson,Tulio de Oliveira,Marion Vermeulen,Karin van der Berg,Karin van der Berg,Theresa M. Rossouw,Michael T. Boswell,Veronica Ueckermann,Susan Meiring,Anne von Gottberg,Anne von Gottberg,Cheryl Cohen,Cheryl Cohen,Lynn Morris,Lynn Morris,Jinal N. Bhiman,Jinal N. Bhiman,Penny L. Moore,Penny L. Moore +25 more
TL;DR: In this article, the authors show that SARS-CoV-2 501Y.1.V2 spike protein completely escapes three classes of therapeutically relevant antibodies and exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma.
Journal ArticleDOI
Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection.
Zijun Wang,Frauke Muecksch,Dennis Schaefer-Babajew,Shlomo Finkin,Charlotte Viant,Christian Gaebler,Hans Heinrich Hoffmann,Christopher O. Barnes,Melissa Cipolla,Victor A. Ramos,Thiago Y. Oliveira,Alice Cho,Fabian Schmidt,Justin Da Silva,Eva Bednarski,Lauren C. Aguado,Jim Yee,Mridushi Daga,Martina Turroja,Katrina G. Millard,Mila Jankovic,Anna Gazumyan,Anna Gazumyan,Zhen Zhao,Charles M. Rice,Paul D. Bieniasz,Paul D. Bieniasz,Marina Caskey,Theodora Hatziioannou,Michel C. Nussenzweig,Michel C. Nussenzweig +30 more
TL;DR: In the absence of vaccination, antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable between 6 and 12 months after infection.
Posted ContentDOI
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
Constantinos Kurt Wibmer,Frances Ayres,Tandile Hermanus,Mashudu Madzivhandila,Prudence Kgagudi,Brent Oosthuysen,Bronwen E. Lambson,Bronwen E. Lambson,Tulio de Oliveira,Marion Vermeulen,Karin van der Berg,Karin van der Berg,Theresa M. Rossouw,Michael T. Boswell,Veronica Ueckermann,Susan Meiring,Anne von Gottberg,Anne von Gottberg,Cheryl Cohen,Cheryl Cohen,Lynn Morris,Lynn Morris,Jinal N. Bhiman,Jinal N. Bhiman,Penny L. Moore,Penny L. Moore +25 more
TL;DR: SARS-CoV-2 501Y.V2 (B.1.351), a lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein this article.
Journal ArticleDOI
Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.
Paul-Albert Koenig,Hrishikesh Das,Hejun Liu,Beate M. Kümmerer,Florian N. Gohr,Lea-Marie Jenster,Lisa D. J. Schiffelers,Yonas M. Tesfamariam,Miki Uchima,Jennifer Deborah Wuerth,Karl Gatterdam,Natalia Ruetalo,Maria H Christensen,Caroline I. Fandrey,Sabine Normann,Jan M. P. Tödtmann,Steffen Pritzl,Leo Hanke,Jannik Boos,Meng Yuan,Xueyong Zhu,Jonathan L. Schmid-Burgk,Hiroki Kato,Michael Schindler,Ian A. Wilson,Matthias Geyer,Kerstin U. Ludwig,B. Martin Hallberg,Nicholas C. Wu,Florian I. Schmidt +29 more
TL;DR: In this paper, the authors used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes of the SARS-CoV-2 spike protein.
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