SARS-CoV-2 spike protein heptad repeat domains (HR1/HR2)

The SARS-CoV-2 spike protein heptad repeat domains, HR1 and HR2, are highly conserved regions within the S2 subunit of the spike (S) glycoprotein (UniProt: P0DTC2). These domains play a pivotal role in the viral entry process by mediating the fusion between the viral envelope and the host cell membrane. Upon binding of the S1 subunit to the host ACE2 receptor and subsequent cleavage by proteases like TMPRSS2, the S2 subunit undergoes a major conformational rearrangement. During this process, three HR1 helices and three HR2 helices assemble into a six-helix bundle (6HB) fusion core, which pulls the membranes together (PubMed: 32231345). This mechanism is a critical bottleneck for infection, making the HR domains attractive targets for therapeutic intervention. Fusion inhibitors, such as the pan-coronavirus peptide EK1 and its derivative EK1C4, work by binding to the HR1 groove and preventing the HR1-HR2 interaction, thereby blocking viral entry (PubMed: 32366481). Because the HR1 and HR2 sequences are highly conserved across various SARS-CoV-2 variants and other betacoronaviruses, they represent a robust target for broad-spectrum antiviral development. Therapeutic challenges include the short half-life of peptide-based inhibitors and the need for effective delivery systems to the respiratory tract.

Other names

Heptad repeat 1Heptad repeat 2HR1 domainHR2 domainS2 fusion coreSARS-CoV-2 S2 subunit heptad repeats

Fusion inhibition by binding to the HR1 or HR2 domains to prevent the formation of the six-helix bundle (6HB) required for viral-host membrane fusion.