SARS-CoV-2 spike protein (non-ACE2-binding motif epitopes) (SARS-CoV-2 S protein (non-RBM))

The SARS-CoV-2 spike (S) protein is a trimeric class I fusion protein that facilitates viral entry into host cells by mediating both attachment to the ACE2 receptor and fusion with the host cell membrane (Nature, 2020). While the receptor-binding motif (RBM) within the receptor-binding domain (RBD) is the primary site for ACE2 interaction, epitopes located outside this motif—such as those in the N-terminal domain (NTD), the conserved core of the RBD, and the S2 subunit—are critical therapeutic targets (Science, 2021). These non-RBM epitopes are often more conserved across different sarbecoviruses and SARS-CoV-2 variants, making them ideal for developing broadly neutralizing antibodies (bnAbs) that are less susceptible to mutational escape (Nature Communications, 2022). Monoclonal antibodies like Sotrovimab (S309) target these regions to neutralize the virus by inhibiting the structural rearrangements necessary for membrane fusion or by providing steric hindrance that prevents ACE2 docking indirectly (Nature, 2020). Furthermore, targeting the S2 subunit, which contains the fusion machinery, offers a potential pathway for universal coronavirus therapies due to its high sequence conservation (Science, 2021). Consequently, these epitopes are high-priority targets for the next generation of variant-proof vaccines and therapeutic antibodies.

Other names

SARS-CoV-2 spike glycoproteinS protein non-RBM epitopesN-terminal domain (NTD) epitopesS2 subunit epitopesConserved spike epitopesSpike protein stem helixSpike protein fusion peptide

Neutralization of viral entry by inhibiting conformational changes required for membrane fusion or by sterically hindering receptor engagement despite being outside the direct binding interface.