Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged, causing significant global health impact.
• Coronavirus spike (S) glycoproteins are crucial for viral entry and are primary targets for neutralizing antibodies.
• Understanding the SARS-CoV-2 S protein's structure and function is vital for developing medical countermeasures.

Purpose of the Study:

• To investigate the cell entry mechanism of SARS-CoV-2.
• To characterize the structural features of the SARS-CoV-2 S glycoprotein.
• To explore potential therapeutic strategies targeting the S protein.

Main Methods:

• Analysis of SARS-CoV-2 S protein interaction with human Angiotensin-Converting Enzyme 2 (ACE2).
• Determination of cryo-electron microscopy (cryo-EM) structures of the SARS-CoV-2 S ectodomain trimer.
• Assessment of antibody neutralization against SARS-CoV-2 S-mediated viral entry.

Main Results:

• SARS-CoV-2 S utilizes ACE2 for cell entry, with similar binding affinity to human ACE2 as SARS-CoV S.
• A novel furin cleavage site was identified at the S1/S2 subunit boundary of SARS-CoV-2 S, distinguishing it from other coronaviruses.
• Cryo-EM structures revealed the trimeric ectodomain of the SARS-CoV-2 S protein.
• Murine polyclonal antibodies against SARS-CoV S demonstrated potent inhibition of SARS-CoV-2 S-mediated cell entry.

Conclusions:

• The findings provide a structural blueprint for designing vaccines and inhibitors against SARS-CoV-2.
• The presence of a furin cleavage site may contribute to the efficient spread of SARS-CoV-2.
• Cross-neutralizing antibodies targeting conserved S epitopes offer a promising avenue for therapeutic interventions and vaccination strategies.