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Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

58 Pages Posted: 1 Jun 2020 Publication Status: Review Complete

See all articles by Jiandong Huo

Jiandong Huo

University of Oxford - Division of Structural Biology

Yuguang Zhao

University of Oxford - Division of Structural Biology

Jingshan Ren

University of Oxford - Division of Structural Biology

Daming Zhou

University of Oxford - Division of Structural Biology

Helen Duyvesteyn

University of Oxford - Division of Structural Biology

Helen Ginn

Public Health England - National Infection Service

Loic Carrique

University of Oxford - Division of Structural Biology

Tomas Malinauskas

University of Oxford - Division of Structural Biology

Reinis Ruza

University of Oxford - Division of Structural Biology

Pranav Shah

University of Oxford - Division of Structural Biology

Tiong Tan

University of Oxford - MRC Human Immunology Unit

Pramila Rijal

University of Oxford - MRC Human Immunology Unit

Naomi Coombes

Public Health England - National Infection Service

Kevin Bewley

Public Health England - National Infection Service

Julia Tree

Public Health England - National Infection Service

Julika Radecke

Diamond Light Source - Harwell Science and Innovation Campus

Neil G. Paterson

Diamond Light Source - Harwell Science and Innovation Campus

Piyasa Supasa

University of Oxford - Wellcome Trust Centre for Human Genetics

Juthathip Mongkolsapaya

University of Oxford - Wellcome Trust Centre for Human Genetics

Gavin Screaton

University of Oxford - Wellcome Trust Centre for Human Genetics

Miles Carroll

Public Health England - National Infection Service

Alain Townsend

University of Oxford - MRC Human Immunology Unit

Elizabeth Fry

University of Oxford - Division of Structural Biology

Raymond Owens

University of Oxford - Division of Structural Biology

David I. Stuart

University of Oxford - Division of Structural Biology

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Multiple version iconThere are 2 versions of this paper

Abstract

There are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 A of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.

Funding: This work was supported by a grant from the CAMS-Oxford Institute to D.I.S. E.E.F and J.Ren are supported by the Wellcome Trust (101122/Z/13/Z), Y.Z. by Cancer Research UK (C375/A17721) and D.I.S. and E.E.F. by the UK Medical Research Council (MR/N00065X/1). J.H. is supported by a grant from the EPA Cephalosporin Fund. PPUK is funded by the Rosalind Franklin Institute EPSRC Grant no. EP/S025243/1. The National Institute for Health Research Biomedical Research Centre Funding Scheme supports G.R.S. together with the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002), which also supports D.I.S. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z). T.M. is supported by Cancer Research UK grants C20724/A14414 and C20724/A26752 to Christian Siebold. This is a contribution from the UK Instruct-ERIC Centre. The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z). Virus used for the neutralisation assays was a gift from Julian Druce, Doherty Centre, Melbourne, Australia.

Conflict of Interest: The authors declare no competing interests.

Keywords: SARS-CoV-2, Spike, X-ray crystallography, Cryo-EM, Neutralisation, Monoclonal antibody, neutralising monoclonal antibody, COVID-19

Suggested Citation

Huo, Jiandong and Zhao, Yuguang and Ren, Jingshan and Zhou, Daming and Duyvesteyn, Helen and Ginn, Helen and Carrique, Loic and Malinauskas, Tomas and Ruza, Reinis and Shah, Pranav and Tan, Tiong and Rijal, Pramila and Coombes, Naomi and Bewley, Kevin and Tree, Julia and Radecke, Julika and Paterson, Neil G. and Supasa, Piyasa and Mongkolsapaya, Juthathip and Screaton, Gavin and Carroll, Miles and Townsend, Alain and Fry, Elizabeth and Owens, Raymond and Stuart, David I., Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike. Available at SSRN: https://ssrn.com/abstract=3613273 or http://dx.doi.org/10.2139/ssrn.3613273
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jiandong Huo

University of Oxford - Division of Structural Biology

United Kingdom

Yuguang Zhao

University of Oxford - Division of Structural Biology

United Kingdom

Jingshan Ren

University of Oxford - Division of Structural Biology

United Kingdom

Daming Zhou

University of Oxford - Division of Structural Biology

United Kingdom

Helen Duyvesteyn

University of Oxford - Division of Structural Biology

United Kingdom

Helen Ginn

Public Health England - National Infection Service

United Kingdom

Loic Carrique

University of Oxford - Division of Structural Biology

United Kingdom

Tomas Malinauskas

University of Oxford - Division of Structural Biology

United Kingdom

Reinis Ruza

University of Oxford - Division of Structural Biology

United Kingdom

Pranav Shah

University of Oxford - Division of Structural Biology

United Kingdom

Tiong Tan

University of Oxford - MRC Human Immunology Unit

Oxford, Oxfordshire, England
United Kingdom

Pramila Rijal

University of Oxford - MRC Human Immunology Unit

Oxford, Oxfordshire, England
United Kingdom

Naomi Coombes

Public Health England - National Infection Service

United Kingdom

Kevin Bewley

Public Health England - National Infection Service

United Kingdom

Julia Tree

Public Health England - National Infection Service

United Kingdom

Julika Radecke

Diamond Light Source - Harwell Science and Innovation Campus

United Kingdom

Neil G. Paterson

Diamond Light Source - Harwell Science and Innovation Campus

United Kingdom

Piyasa Supasa

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Juthathip Mongkolsapaya

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Gavin Screaton

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Miles Carroll

Public Health England - National Infection Service

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

Alain Townsend

University of Oxford - MRC Human Immunology Unit ( email )

Oxford, Oxfordshire, England
United Kingdom

Elizabeth Fry

University of Oxford - Division of Structural Biology

United Kingdom

Raymond Owens

University of Oxford - Division of Structural Biology

United Kingdom

David I. Stuart (Contact Author)

University of Oxford - Division of Structural Biology ( email )

United Kingdom

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