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
More filters
Posted ContentDOI
Nanobody-Functionalized Cellulose for Capturing and Containing SARS-CoV-2
TL;DR: In this paper, a bifunctional fusion protein consisting of a cellulose-binding domain and a nanobody targeting the receptor binding domain of SARS-CoV-2 was developed.
Posted Content
Conformational variability of loops in the SARS-CoV-2 spike protein
Samuel W. K. Wong,Zongjun Liu +1 more
TL;DR: In this paper, the conformations of loops in the SARS-CoV-2 spike (S) protein were studied based on the available Protein Data Bank (PDB) structures.
Posted ContentDOI
Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody
Dmitri Dormeshkin,Michail A. Shapira,S. Yu. Dubovik,Anton Kavaleuski,M. I. Katsin,Alexandr A. Migas,Alexander Meleshko,S.E. Semyonov +7 more
TL;DR: This work identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD) by screening synthetic humanized antibody library with more than 1011 diversity, and found H7-Fc and G12×3-fc binders with the affinities in nM and pM range respectively.
Journal ArticleDOI
Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains
Chun Chen,James W. Saville,Michelle Marti,Alexandra Schäfer,Mary Hongying Cheng,Dhiraj Mannar,Xing Zhu,Alison M. Berezuk,Anupam Banerjee,Michele D. Sobolewski,A. Kim,Benjamin R. Treat,Priscila Mayrelle da Silva Castanha,Nathan Enick,Kevin McCormick,Xianglei Liu,Cynthia Adams,M. G. Hines,Zehua Sun,Weizao Chen,Jana L. Jacobs,Simon M. Barratt-Boyes,John W. Mellors,Ralph S. Baric,Ivet Bahar,Dimiter S. Dimitrov,Sriram Subramaniam,David R. Martinez,Wei Liu +28 more
TL;DR: In this paper , a human VH domain, F6, was characterized by sequentially panning large phage-displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations.
References
More filters
Journal ArticleDOI
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang,Yeming Wang,Xingwang Li,Lili Ren,Jianping Zhao,Yi Hu,Li Zhang,Guohui Fan,Jiuyang Xu,Xiaoying Gu,Zhenshun Cheng,Ting Yu,Jia'an Xia,Yuan Wei,Wenjuan Wu,Xuelei Xie,Wen Yin,Li Hui,Min Liu,Yan Xiao,Hong Gao,Li Guo,Jungang Xie,Guang-Fa Wang,Rongmeng Jiang,Zhancheng Gao,Qi Jin,Jianwei Wang,Bin Cao +28 more
TL;DR: The epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of patients with laboratory-confirmed 2019-nCoV infection in Wuhan, China, were reported.
Journal ArticleDOI
Coot: model-building tools for molecular graphics.
Paul Emsley,Kevin Cowtan +1 more
TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Journal ArticleDOI
A Novel Coronavirus from Patients with Pneumonia in China, 2019.
Na Zhu,Dingyu Zhang,Wenling Wang,Xingwang Li,Bo Yang,Jingdong Song,Xiang Zhao,Baoying Huang,Weifeng Shi,Roujian Lu,Peihua Niu,Faxian Zhan,Xuejun Ma,Dayan Wang,Wenbo Xu,Wenbo Xu,Guizhen Wu,George F. Gao,Wenjie Tan +18 more
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Journal ArticleDOI
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Paul D. Adams,Paul D. Adams,Pavel V. Afonine,Gábor Bunkóczi,Vincent B. Chen,Ian W. Davis,Nathaniel Echols,Jeffrey J. Headd,Li-Wei Hung,Gary J. Kapral,Ralf W. Grosse-Kunstleve,Airlie J. McCoy,Nigel W. Moriarty,Robert D. Oeffner,Randy J. Read,David S. Richardson,Jane S. Richardson,Thomas C. Terwilliger,Peter H. Zwart +18 more
TL;DR: The PHENIX software for macromolecular structure determination is described and its uses and benefits are described.
Journal ArticleDOI
Phaser crystallographic software
Airlie J. McCoy,Ralf W. Grosse-Kunstleve,Paul D. Adams,Martyn Winn,Laurent C. Storoni,Randy J. Read +5 more
TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Related Papers (5)
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Christopher O. Barnes,Claudia A. Jette,Morgan E. Abernathy,Kim Marie A. Dam,Shannon R. Esswein,Harry B. Gristick,Andrey G. Malyutin,Naima G. Sharaf,Kathryn E. Huey-Tubman,Yu E. Lee,Davide F. Robbiani,Davide F. Robbiani,Michel C. Nussenzweig,Michel C. Nussenzweig,Anthony P. West,Pamela J. Bjorkman +15 more
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.
Dora Pinto,Young-Jun Park,Martina Beltramello,Alexandra C. Walls,M. Alejandra Tortorici,M. Alejandra Tortorici,Siro Bianchi,Stefano Jaconi,Katja Culap,Fabrizia Zatta,Anna De Marco,Alessia Peter,Barbara Guarino,Roberto Spreafico,Elisabetta Cameroni,James Brett Case,Rita E. Chen,Colin Havenar-Daughton,Gyorgy Snell,Amalio Telenti,Herbert W. Virgin,Antonio Lanzavecchia,Michael S. Diamond,Katja Fink,David Veesler,Davide Corti +25 more