Severe acute respiratory syndrome coronavirus 2 spike protein (non-ACE2-binding receptor binding domain and quaternary epitopes) (SARS-CoV-2 S protein)

The SARS-CoV-2 spike (S) protein is a trimeric Class I fusion protein responsible for viral attachment and entry into host cells (Wrapp et al., Science 2020). While the receptor-binding motif (RBM) is the primary site for ACE2 interaction, non-ACE2-binding regions within the receptor-binding domain (RBD) and quaternary epitopes—which span multiple protomers—serve as vital targets for neutralizing antibodies (Pinto et al., Nature 2020). These epitopes are often more conserved across different sarbecoviruses, making them ideal targets for "variant-proof" therapeutics like Sotrovimab, which binds a conserved glycan-containing epitope (Cathcart et al., Nature 2022). Quaternary epitopes are structurally complex and depend on the native trimeric conformation of the spike protein, often involving the N-terminal domain (NTD) or the S2 subunit (Tortorici et al., Nature 2020). Drugs targeting these sites function by preventing the conformational transitions required for membrane fusion or by sterically blocking the virus's ability to engage with the host cell surface (Hansen et al., Science 2020). Additionally, these antibodies can recruit the host immune system through Fc-mediated effector functions to clear infected cells (Case et al., Cell Host & Microbe 2020). Understanding these epitopes is essential for the design of next-generation vaccines and therapeutics capable of maintaining efficacy against emerging SARS-CoV-2 variants (Starr et al., Nature 2021).

Other names

SARS-CoV-2 spike glycoproteinS-proteinNon-RBM RBD epitopesQuaternary spike epitopesSARS-CoV-2 S2 subunitSARS-CoV-2 NTD

Neutralization of viral entry by sterically hindering membrane fusion or receptor attachment (Wrapp et al., Science 2020), and induction of Fc-mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) (Case et al., Cell Host & Microbe 2020).