SARS-CoV-2 spike protein (non-RBD regions) (S protein (non-RBD))

The SARS-CoV-2 spike (S) protein is a class I fusion protein that facilitates viral entry into host cells by binding to the ACE2 receptor and mediating membrane fusion [1, 11]. While the receptor-binding domain (RBD) is the most common target for neutralizing antibodies, the non-RBD regions—comprising the N-terminal domain (NTD) and the S2 subunit—are essential for the structural integrity and functional transitions of the spike [4, 13]. The NTD is involved in initial cell surface attachment and allosteric regulation, while the S2 subunit contains the fusion peptide (FP) and heptad repeats (HR1 and HR2) that drive the fusion of the viral envelope with the host cell membrane [1, 18]. Because these regions are more conserved across variants than the RBD, they are prime targets for broad-spectrum monoclonal antibodies and fusion inhibitors [4, 5, 13]. Therapeutic strategies include NTD-targeting antibodies that block attachment and S2-targeting peptides or antibodies that prevent the conformational changes necessary for membrane fusion [4, 6, 12]. Additionally, a conserved fatty acid-binding pocket in the spike protein has been identified as a potential target for small molecules to lock the protein in a non-infectious "closed" state [2, 3]. These non-RBD targets offer a promising approach to overcoming the immune escape observed with RBD-focused therapies [13, 16].

Other names

N-terminal domain (NTD)S2 subunitFusion peptide (FP)Heptad repeat 1 (HR1)Heptad repeat 2 (HR2)S1/S2 cleavage siteStem helix (SH)Fatty acid-binding pocket

Inhibition of viral entry by blocking attachment or membrane fusion.