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Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

Our take —

This study exhibits that the efficacy of using a SARS-CoV candidate vaccine for prophylaxis against SARS-CoV-2 is debatable, and that further investigation is warranted. While the research in this particular paper shows that the immunogenicity of the S-protein in SARS-CoV and SARS-CoV-2 differ, it also points out that other areas of the C-terminal domain and the S-protein itself may have more promising potential for vaccine development.

Study design

Other

Study population and setting

This study utilized immunostaining and flow cytometry to identify the SARS-CoV-2 C-terminal domain (CTD), and used X-ray crystallography to solve a 2.5 Angstrom crystal structure of the domain in complex with hACE2. Monocolonal antibodies (mAbs) specific to the SARS-RBD were also tested for reactivity to the SARS-CoV-2 S protein.

Summary of Main Findings

SARS-CoV-2 interacts with the human angiotensin converting enzyme 2 (hACE2) via the S protein portion of its CTD. The authors were able to resolve a 2.5 Angstrom structure of the SARS-CoV-2-CTD in complex with the hACE2 receptor. It was found that this CTD has a stronger binding affinity for hACE2 than the SARS-RBD, despite large sequence and structural similarities, and that the SARS-CoV-2-CTD is antigenically distinct from the SARS-receptor binding domain.

Study Strengths

This study employs several different techniques to investigate the structure and binding of the SARS-CoV-2 CTD. Staining images are clear showing co-localization of the CTD and hACE2, and the crystal structure is comprehensive. Comparisons between the SARS-CoV-2 and SARS-CoV CTDs were made at various levels, including nucleotide sequence, protein structure, and electrostatic surface potential. mAbs specific to SARS-CoV-RBD were also employed in order to test the similarity of immunogenicity of the SARS-CoV-2-CTD. Overall, this study was well-rounded.

Limitations

Only SARS-CoV-RBD mAbs were tested against the SARS-CoV-2 CTD, but in the discussion it was mentioned that other emerging studies are finding some neutralizing potential against SARS-CoV-2 from polyclonal Abs from mice and patients with SARS-CoV. Therefore, further investigation is necessary.

Value added

This study clearly delineates the similarities and differences between the binding of SARS-CoV-2 and SARS-CoV to hACE2, and demonstrates that the epitopes on their S-proteins differ in immunogenicity.