SARS-CoV-2 spike protein heptad repeat (HR) (HR)

The SARS-CoV-2 spike protein heptad repeat (HR) regions, specifically HR1 and HR2, are critical structural components of the S2 subunit that mediate the fusion between the viral envelope and the host cell membrane (Xia et al., 2020, Cell Research). Following the initial attachment of the S1 subunit to the ACE2 receptor and subsequent proteolytic priming, the HR1 and HR2 domains undergo a dramatic conformational rearrangement to form a highly stable six-helix bundle (6HB) (Huang et al., 2020, Acta Pharmacologica Sinica). This 6HB formation brings the viral and cellular membranes into close proximity, facilitating the formation of a fusion pore and the subsequent release of the viral genome into the cytoplasm (Zhu et al., 2020, Science Advances). Because the HR regions are highly conserved across various coronaviruses, they serve as a primary target for the development of broad-spectrum fusion inhibitors (Xia et al., 2020, Cell Research). Therapeutic agents, such as the peptide-based inhibitor EK1 and its lipid-conjugated version EK1C4, work by binding to the HR1 domain and sterically blocking its interaction with HR2, thereby preventing 6HB assembly (Zhu et al., 2020, Science Advances). Despite their high potency, the clinical application of these inhibitors faces challenges including the potential for viral resistance mutations and the inherent pharmacokinetic limitations of peptide drugs (Outlaw et al., 2020, Journal of Biological Chemistry).

Other names

Heptad repeat 1Heptad repeat 2HR1HR2S2 subunit heptad repeatSARS-CoV-2 S2 heptad repeat

Fusion inhibition via competitive binding to the HR1 or HR2 domains, preventing the formation of the six-helix bundle (6HB) required for membrane fusion and viral entry (Xia et al., 2020, Cell Research).