SARS-CoV-2 spike glycoprotein non-receptor binding domain neutralizing epitopes (S-non-RBD epitopes)

The SARS-CoV-2 spike (S) glycoprotein is the primary mediator of viral entry and the main target for the host immune response (Harvey et al., 2021, Nature Reviews Microbiology). While the receptor-binding domain (RBD) is the most frequent target for neutralizing antibodies, non-RBD neutralizing epitopes located in the N-terminal domain (NTD) and the S2 subunit are increasingly recognized as vital therapeutic targets (McCallum et al., 2021, Cell). NTD-directed antibodies can neutralize the virus by inhibiting viral attachment to alternative receptors or by sterically hindering the interaction between the RBD and the ACE2 receptor (Chi et al., 2020, Science). Epitopes within the S2 subunit, such as the fusion peptide and the stem helix, are highly conserved across various coronaviruses, making them ideal targets for broadly neutralizing antibodies (bnAbs) that can withstand viral evolution and variant emergence (Pinto et al., 2021, Science). Targeting these non-RBD regions offers a promising strategy for developing universal vaccines and therapeutic monoclonal antibodies that maintain efficacy against diverse SARS-CoV-2 variants and other sarbecoviruses (Zhou et al., 2022, Nature).

Other names

NTD neutralizing epitopesS2 subunit neutralizing epitopesN-terminal domain epitopesFusion peptide epitopesStem helix epitopesConserved spike epitopes

Neutralization of viral infection by blocking N-terminal domain-mediated attachment to co-receptors, inhibiting S1/S2 or S2' proteolytic cleavage, or preventing the conformational rearrangements of the S2 subunit required for membrane fusion.