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

The SARS-CoV-2 spike protein non-ACE2-dependent epitopes are antigenic regions on the viral spike (S) protein that do not overlap with the primary Angiotensin-Converting Enzyme 2 (ACE2) binding site (Harvey et al., Nature Reviews Microbiology, 2021). These epitopes are predominantly found in the N-terminal domain (NTD) of the S1 subunit and throughout the S2 subunit, which facilitates membrane fusion (Chi et al., Science, 2020; Shah et al., 2021). While many potent neutralizing antibodies target the receptor-binding motif (RBM) to block ACE2 interaction, non-ACE2-dependent epitopes are often more conserved across different SARS-CoV-2 variants and other sarbecoviruses (Pinto et al., Nature, 2020). Therapeutic agents targeting these sites, such as the monoclonal antibody Sotrovimab, often provide broader protection by binding to conserved lateral or cryptic epitopes (McCallum et al., Science, 2021). The mechanism of action for drugs hitting these targets typically involves preventing the structural rearrangements of the spike protein necessary for viral-cell fusion or sterically hindering access to the host cell surface (Veesler et al., 2020). These epitopes are also significant for the development of variant-proof vaccines that aim to elicit a broader immune response than those focusing solely on the highly mutable ACE2-binding interface (Wang et al., 2022).

Other names

N-terminal domain (NTD) epitopesS2 subunit epitopesNon-RBM epitopesConserved spike epitopesSARS-CoV-2 NTDSARS-CoV-2 S2 subunitCryptic spike epitopes

Neutralization of viral infection by inhibiting proteolytic processing, preventing conformational changes required for membrane fusion, or blocking attachment to alternative host cell co-receptors.