Severe acute respiratory syndrome coronavirus 2 spike glycoprotein non-receptor binding domain regions (SARS-CoV-2 S non-RBD)

The SARS-CoV-2 spike (S) glycoprotein is a homotrimeric class I fusion protein that mediates viral entry into host cells [1]. While the receptor-binding domain (RBD) is the primary target for most neutralizing antibodies, the non-RBD regions—comprising the N-terminal domain (NTD) of the S1 subunit and the entire S2 subunit—are critical for viral function and represent key therapeutic targets [2, 4]. The NTD is involved in initial cell surface attachment and facilitates the conformational transitions required for ACE2 binding, while the S2 subunit contains the fusion machinery, including the fusion peptide and heptad repeats, which mediate the merging of viral and host membranes [1, 3]. Targeting these regions is particularly valuable for developing broadly neutralizing antibodies and universal vaccines, as the S2 subunit is significantly more conserved across variants and other coronaviruses than the rapidly mutating RBD [3, 4]. Therapeutic strategies focusing on non-RBD regions aim to block viral attachment, prevent the structural rearrangements required for fusion, or induce Fc-mediated effector functions to clear infected cells [2, 5].

Other names

N-terminal domainNTDS2 subunitFusion peptideHeptad repeat 1Heptad repeat 2Spike protein non-RBD

Inhibition of viral-host membrane fusion, blocking of NTD-mediated attachment, stabilization of the pre-fusion spike trimer, and induction of Fc-mediated effector functions.