Coronavirus spike protein non-receptor binding domain epitopes (Non-RBD epitopes)

Non-RBD epitopes on the SARS-CoV-2 spike protein and related coronaviruses are antigenic regions located outside the receptor-binding domain, primarily within the N-terminal domain (NTD) and the S2 subunit (Chi et al., Science 2020). While the RBD is the most common target for neutralizing antibodies, it is highly susceptible to mutations that allow the virus to escape the immune system. Non-RBD epitopes, particularly those in the S2 fusion machinery and the stem helix, tend to be more conserved across different viral variants and even across different species of betacoronaviruses (Pinto et al., Science 2021). Therapeutic agents targeting these sites, such as certain broadly neutralizing antibodies, work by preventing the conformational changes necessary for viral-host membrane fusion or by sterically interfering with the infection process (Sauer et al., Nat Struct Mol Biol 2021). These epitopes are currently a major focus for the development of universal coronavirus vaccines and therapeutics designed to maintain efficacy against emerging variants (McCallum et al., Science 2021). By targeting these stable regions, researchers hope to provide broader and more durable protection than that offered by first-generation RBD-centric interventions.

Other names

N-terminal domain (NTD) epitopesS2 subunit epitopesSpike protein stem regionFusion peptide epitopesConserved coronavirus epitopesNon-RBM epitopes

Neutralization of viral infection by inhibiting membrane fusion, blocking conformational changes of the spike protein, or sterically hindering receptor interaction through binding to the N-terminal domain or S2 subunit.