Severe acute respiratory syndrome coronavirus 2 spike protein S2 subunit and non-receptor binding domain epitopes (SARS-CoV-2 S2/non-RBD)

The SARS-CoV-2 spike protein S2 subunit and non-receptor binding domain (non-RBD) epitopes are essential components of the viral entry mechanism. The S2 subunit is responsible for the fusion of the viral envelope with the host cell membrane, a process triggered after the S1 subunit binds to the ACE2 receptor (UniProt P0DTC2). Unlike the highly variable receptor-binding domain (RBD), the S2 subunit and certain non-RBD regions like the N-terminal domain (NTD) are relatively conserved across different SARS-CoV-2 variants and other coronaviruses (Harvey et al., 2021). This conservation makes them attractive targets for broadly neutralizing antibodies and "universal" vaccine development. Monoclonal antibodies targeting the NTD, such as 4A8, or the S2 subunit, such as S2P6, work by preventing the conformational changes required for membrane fusion or by sterically hindering viral attachment (Chi et al., 2020; Pinto et al., 2021). Most current COVID-19 vaccines, including BNT162b2 and mRNA-1273, elicit an immune response against the entire spike protein, thereby generating antibodies that target these S2 and non-RBD epitopes. Understanding these regions is crucial for overcoming the challenges posed by viral escape mutations in the RBD. These epitopes provide a pathway for developing therapeutics that maintain efficacy against emerging variants of concern. Therapeutic intervention at these sites often involves blocking the transition from pre-fusion to post-fusion states. Overall, the S2 and non-RBD regions are pivotal for broad-spectrum immunity and long-term pandemic management.

Other names

SARS-CoV-2 S2 subunitSARS-CoV-2 spike protein N-terminal domainSARS-CoV-2 NTDSARS-CoV-2 fusion protein subunitSARS-CoV-2 spike protein S2 domain

Inhibition of viral-host membrane fusion, neutralization of viral infectivity by binding to conserved non-RBD regions, and prevention of spike protein conformational changes.