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

Jiwan Ge, Ruoke Wang, Bin Ju, Qi Zhang, Jing Sun, Peng Chen, Senyan Zhang, Yuling Tian, Sisi Shan, Lin Cheng, Bing Zhou, Shuo Song, Juanjuan Zhao, Haiyan Wang, Xuanling Shi, Qiang Ding, Lei Liu, Jincun Zhao, Zheng Zhang (), Xinquan Wang () and Linqi Zhang ()
Additional contact information
Jiwan Ge: Tsinghua University
Ruoke Wang: Tsinghua University
Bin Ju: Southern University of Science and Technology
Qi Zhang: Tsinghua University
Jing Sun: Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University
Peng Chen: Tsinghua University
Senyan Zhang: Tsinghua University
Yuling Tian: Tsinghua University
Sisi Shan: Tsinghua University
Lin Cheng: Southern University of Science and Technology
Bing Zhou: Southern University of Science and Technology
Shuo Song: Southern University of Science and Technology
Juanjuan Zhao: Southern University of Science and Technology
Haiyan Wang: Southern University of Science and Technology
Xuanling Shi: Tsinghua University
Qiang Ding: Tsinghua University
Lei Liu: Southern University of Science and Technology
Jincun Zhao: Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University
Zheng Zhang: Southern University of Science and Technology
Xinquan Wang: Tsinghua University
Linqi Zhang: Tsinghua University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20501-9

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