Antibody neutralization of SARS-CoV-2 through ACE2 receptor mimicry

• Published in: Nature communications 2021-01, Vol.12 (1), p.250-250, Article 250
• Main Authors: Ge, Jiwan, Wang, Ruoke, Ju, Bin, Zhang, Qi, Sun, Jing, Chen, Peng, Zhang, Senyan, Tian, Yuling, Shan, Sisi, Cheng, Lin, Zhou, Bing, Song, Shuo, Zhao, Juanjuan, Wang, Haiyan, Shi, Xuanling, Ding, Qiang, Liu, Lei, Zhao, Jincun, Zhang, Zheng, Wang, Xinquan, Zhang, Linqi
• Format: Article
• Language: English
• Subjects: 101/1; 13; 13/31; 631/250/254; 631/326/596/4130; ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Binding; Binding Sites; Cell surface; COVID-19 - drug therapy; COVID-19 - immunology; COVID-19 - virology; Crystal structure; Disease Models, Animal; Displays; Drug development; Epitopes; Glycoproteins; HEK293 Cells; Humanities and Social Sciences; Humans; Infections; Mice; Mice, Inbred BALB C; Mimicry; Models, Molecular; Monoclonal antibodies; multidisciplinary; Neutralization; Neutralizing; Protein Binding; Protein Conformation; Receptors; Receptors, Virus - immunology; Receptors, Virus - metabolism; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike glycoprotein; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; Structure-function relationships; Vaccines; Viral diseases; Virus Internalization
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20501-9

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry. Here, the authors compare the crystal structures and investigate the neutralization mechanisms of three neutralizing antibodies against SARS-CoV-2 and find that one antibody, P2C-1F11, closely mimics binding of receptor ACE2 and displays the most potent neutralizing activity in vitro, as well as conferring protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice.