Severe acute respiratory syndrome coronavirus 2 spike protein S2 subunit fusion-associated epitopes (SARS-CoV-2 S2 fusion epitopes)

The SARS-CoV-2 spike fusion-associated epitopes are critical regions within the S2 subunit of the viral spike (S) protein that facilitate the fusion of the viral envelope with the host cell membrane. These epitopes include the fusion peptide (FP), heptad repeat 1 (HR1), heptad repeat 2 (HR2), and the stem helix, which undergo dramatic structural rearrangements to bring the membranes together. Unlike the highly variable receptor-binding domain (RBD) in the S1 subunit, these fusion-associated regions are highly conserved across various SARS-CoV-2 variants and even other coronaviruses, making them attractive targets for broad-spectrum therapeutics. Drugs targeting these epitopes, such as neutralizing antibodies and fusion-inhibiting peptides, work by physically blocking the formation of the six-helix bundle or preventing the insertion of the fusion peptide into the host membrane. Consequently, these epitopes are central to the development of next-generation vaccines and pan-coronavirus antivirals aimed at providing durable protection against emerging variants.

Other names

SARS-CoV-2 S2 subunitSpike protein fusion machineryFusion peptide (FP)Heptad repeat 1 (HR1)Heptad repeat 2 (HR2)Stem helixMembrane proximal external region (MPER)

Neutralizing antibodies bind to conserved epitopes in the S2 subunit to prevent the conformational changes required for membrane fusion, while peptide inhibitors like EK1 mimic the HR2 domain to bind HR1 and block the formation of the six-helix bundle (6-HB) fusion core.