Neutralization of SARS-CoV-2 by destruction of the prefusion Spike
Summary 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 Å 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.Highlights <jats:list list-type="bullet">CR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment.
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 13. März Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huo, Jiandong [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/2020.05.05.079202 |
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| funding: |
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| PPN (Katalog-ID): |
XBI017769728 |
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| 245 | 1 | 0 | |a Neutralization of SARS-CoV-2 by destruction of the prefusion Spike |
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| 520 | |a Summary 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 Å 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.Highlights <jats:list list-type="bullet">CR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment | ||
| 700 | 1 | |a Zhao, Yuguang |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Jingshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Daming |e verfasserin |4 aut | |
| 700 | 1 | |a Duyvesteyn, Helen ME |e verfasserin |4 aut | |
| 700 | 1 | |a Ginn, Helen M |e verfasserin |4 aut | |
| 700 | 1 | |a Carrique, Loic |e verfasserin |4 aut | |
| 700 | 1 | |a Malinauskas, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Ruza, Reinis R |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Pranav NM |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Tiong Kit |e verfasserin |4 aut | |
| 700 | 1 | |a Rijal, Pramila |e verfasserin |4 aut | |
| 700 | 1 | |a Coombes, Naomi |e verfasserin |4 aut | |
| 700 | 1 | |a Bewley, Kevin |e verfasserin |4 aut | |
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| 700 | 1 | |a Paterson, Neil G |e verfasserin |4 aut | |
| 700 | 1 | |a Supasa, Piyasa |e verfasserin |4 aut | |
| 700 | 1 | |a Mongkolsapaya, Juthathip |e verfasserin |4 aut | |
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| 700 | 1 | |a Owens, Raymond J |e verfasserin |4 aut | |
| 700 | 1 | |a Stuart, David I |e verfasserin |4 aut | |
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