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

The SARS-CoV-2 spike (S) protein non-RBD epitopes refer to the antigenic regions of the viral spike glycoprotein located outside the receptor-binding domain (RBD), primarily within the N-terminal domain (NTD) of the S1 subunit and the entirety of the S2 subunit [1, 3]. While the RBD is the most common target for neutralizing antibodies, non-RBD epitopes are critical for viral functions such as initial attachment, conformational triggering, and membrane fusion [14, 15]. The NTD is involved in auxiliary receptor binding and can be targeted by antibodies that prevent the transition from pre-fusion to post-fusion states [1, 10]. The S2 subunit, containing the fusion peptide and heptad repeat regions (HR1 and HR2), is highly conserved across various coronaviruses, making it a prime target for broad-spectrum or pan-coronavirus therapeutics [7, 9]. Experimental drugs targeting these regions include monoclonal antibodies like 4A8 and CV3-25, as well as fusion-inhibiting peptides like EK1 [7, 10, 12]. These agents aim to block viral entry and reduce the severity of COVID-19, particularly against variants that have mutated to escape RBD-targeting immunity [2, 8]. However, challenges include the high mutational frequency of the NTD and the generally lower neutralizing potency of S2-targeting antibodies compared to those targeting the RBD [4, 14].

Other names

N-terminal domain (NTD) epitopesS2 subunit epitopesSARS-CoV-2 S1 non-RBD regionsFusion peptide (FP) epitopesHeptad repeat (HR) epitopesStem helix epitopesSARS-CoV-2 spike protein non-receptor binding domain epitopes

Neutralization of viral entry, inhibition of membrane fusion, prevention of conformational transition, antibody-dependent cellular cytotoxicity (ADCC), and complement fixation.