Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike
By J. Huo, Yuguang Zhao, Jingshan Ren, Daming Zhou, Helen M. E. Duyvesteyn, H. Ginn, L. Carrique, T. Malinauskas, R. Ruza, P. Shah and 14 more. 2020
336 citations recorded by the source corpus.
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 CR3022 neutralises SARS-CoV-2 Neutralisation is by destroying the prefusion SPIKE conformation This antibody may have therapeutic potential alone or with one blocking receptor attachment
Subfields: Animal Science and Zoology, Infectious Diseases
Citations in the corpus
- Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, neutral): “, 2020b), and a recombinant form of one cross-reactive non-neutralizing antibody isolated from a convalescent SARS-CoV-1 patient (rCR3022) (Huo et al., 2020; ter Meulen et al., 2006; Tian et al., 2020; Yuan et al., 2020).”
- Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding (2020, neutral): “Second, the RBD is just one domain of the viral spike, which engages in complex dynamic movements to mediate viral entry (Huo et al., 2020; Walls et al., 2019, 2020; Wrapp et al., 2020b).”
- SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses (2022, neutral): “VhVl and ChCl domains which have the most sequence similarity to previously determined SARS-CoV-2 RBD/Fab structures (Dejnirattisai et al., 2021a, 2021b; Huo et al., 2020; Liu et al., 2021a; Supasa et al., 2021; Zhou et al., 2020, 2021) were used as search models for each of the current structure de”
- Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum (2022, neutral): “REAGENT or RESOURCE SOURCE IDENTIFIER Antibodies Nanobody C1 Huo et al., 2020a N/A Fab Dejnirattisai et al., 2021a N/A IgG Dejnirattisai et al., 2021a; Liu et al., 2021b N/A EY6A mAb Zhou et al., 2020 N/A Regeneron mAbs AstraZeneca Cat#REGN10933, and REGN10987 AstraZeneca mAbs AstraZeneca…”
- Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, neutral): “Second, the RBD is just one domain of the viral spike, which engages in complex dynamic movements to mediate viral entry (Huo et al., 2020; Walls et al., 2019, 2020; Wrapp et al., 2020b).”