A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2
By Xiangyang Chi, R. Yan, Jun Zhang, Guanying Zhang, Yuanyuan Zhang, Meng Hao, Zhe Zhang, Pengfei Fan, Yunzhu Dong, Yilong Yang and 14 more. Science, 2020
1,371 citations recorded by the source corpus.
Hitting SARS-CoV-2 in a new spot A key target for therapeutic antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the spike protein, a trimeric protein complex with each monomer comprising an S1 and an S2 domain that mediate binding to host cells and membrane fusion, respectively. In addition to the receptor binding domain (RBD), S1 has an N-terminal domain (NTD). In searching for neutralizing antibodies, there has been a focus on the RBD. Chi et al. isolated antibodies from 10 convalescent patients and identified an antibody that potently neutralizes the virus but does not bind the RBD. Cryo–electron microscopy revealed the epitope as the NTD. This NTD-targeting antibody may be useful to combine with RBD-targeting antibodies in therapeutic cocktails. Science, this issue p. 650 A region outside of the receptor binding domain of SARS-CoV-2 is targeted by a neutralizing antibody. Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.
Subfields: Animal Science and Zoology, Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/8d8071ffec6cb22b088a0b22b40afddf96ca6593
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In Infectious Diseases
Citations in the corpus
- Structural Analysis of the SARS-CoV-2 Omicron Variant Proteins (2021, background): “84 However, the Omicron S1 NTD structure showed that many epitopes that could be 85 recognized by various antibodies are altered in comparison to the original strain (PDB:7C2L [11]) 86 (Figure 1K).”
- Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein (2021, neutral): “Several groups have described mAbs targeting non-RBD regions, but their epitopes, mechanisms of action, and protective activity in vivo remain unclear (Chi et al., 2020; Liu et al., 2020a).”
- Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum (2021, positive): “A second class of potently neutralizing antibodies bind to a site on the NTD called the supersite; these antibodies do not block interaction with ACE2, and their mode of neutralization is less well understood (Cerutti et al., 2021; Chi et al., 2020; Dejnirattisai et al., 2021a).”
- Molecular Architecture of the SARS-CoV-2 Virus (2020, positive): “However, the sparsely packed spikes on the viral envelope are also more vulnerable to neutralizing antibodies that bind the otherwise less accessible domains (Chi et al., 2020) or glycan holes (Walls et al.”
- SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development (2020, background): “There are hydrogen bonds between K150 and 4A8-Y111, H146 and 4A8-T30 (Chi et al., 2020).”
- Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum (2022, positive): “All of these antibodies interact with the RBD, with the exception of Omi-41, which binds the NTD and specifically neutralizes BA.1, BA.1.1, and BA.3 but not BA.2 or BA.4/5 (for unknown reasons, Omi41 can neutralize wild-type (WT) Victoria virus but not Victoria pseudovirus) (Nutalai et al., 2022).”
- Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies (2021, background): “, 2020a) and the variable domain heavy and light chain sequences for r4A8 were obtained from Genbank GI 1864383732 and 1864383733 (Chi et al., 2020) and produced on a human IgG1 and IgK background, respectively.”
- A human coronavirus evolves antigenically to escape antibody immunity (2020, background): “…elicited by infection primarily targets the RBD (Piccoli et al., 2020), mutations to the NTD also reduce neutralization by some antibodies and sera (Chi et al., 2020; Kemp et al., 2020; Liu et al., 2020a; McCarthy et al., 2020; Weisblum et al., 2020; Zhou et al., 2019)—and some regions of the NTD…”