SARS-CoV-2 spike glycoprotein S2 subunit, Heptad Repeat 2 membrane-proximal quaternary epitope (HR2 MPQE)

The SARS-CoV-2 spike glycoprotein S2 subunit contains the Heptad Repeat 2 (HR2) domain, which is essential for the viral fusion process. The membrane-proximal quaternary epitope (MPQE) is a highly conserved site within the HR2 trimer that remains relatively stable across various SARS-CoV-2 variants and other sarbecoviruses. During infection, the S2 subunit undergoes a significant conformational change where HR2 interacts with Heptad Repeat 1 (HR1) to form a six-helix bundle, a process that facilitates the fusion of the viral envelope with the host cell membrane. Therapeutic agents, such as the nanobody R3DC23 (developed as XVR013), target this quaternary epitope to clamp the HR2 monomers together, locking the spike protein in its prefusion state. This mechanism effectively blocks the transition to the post-fusion form and inhibits viral entry. Due to its high conservation, this epitope is a key target for developing broad-spectrum therapeutics and vaccines capable of providing protection against a wide range of coronaviruses.

Other names

S2-HR2 quaternary epitopeMembrane-proximal HR2 epitopeHR2 trimer epitopeS2 stem-proximal epitopeHR2 membrane-proximal region

Inhibition of viral membrane fusion by locking the HR2 trimer in a prefusion conformation and preventing six-helix bundle (6HB) formation.