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

The SARS-CoV-2 spike protein S2 subunit is a class I viral fusion protein that mediates the critical step of membrane fusion between the virus and the host cell [1][4]. Following the cleavage of the spike protein and the shedding of the S1 subunit, the S2 subunit undergoes a massive conformational rearrangement to insert its fusion peptide into the host membrane [3]. This process involves the assembly of the heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains into a stable six-helix bundle (6HB), which pulls the viral and cellular membranes together to facilitate genome entry [2]. The trimer interface within the S2 subunit is essential for maintaining the structural integrity of the spike complex in its pre-fusion state and coordinating the transition to the post-fusion state [4]. Because the S2 subunit is more highly conserved than the S1 subunit across different SARS-CoV-2 variants and other betacoronaviruses, it is a primary target for broad-spectrum fusion inhibitors and universal vaccines [5]. Therapeutic strategies focusing on this interface aim to physically block the formation of the 6HB or stabilize the pre-fusion conformation, effectively neutralizing the virus's ability to infect host cells [2][5]. Small molecules, lipopeptides like EK1C4, and specific neutralizing antibodies such as S2P6 are currently being investigated for their ability to disrupt these processes [2][5]. Targeting the S2 subunit offers a potential solution to the challenge of rapid viral evolution frequently observed in the receptor-binding domain of the S1 subunit.

Other names

SARS-CoV-2 S2 subunitSpike glycoprotein S2Surface glycoprotein S2 subunitSARS-CoV-2 S2 trimer interfaceS2 fusion proteinSARS-CoV-2 S2 domain

Inhibition of the conformational transition from the pre-fusion to the post-fusion state by blocking the formation of the six-helix bundle (6HB) between the heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains [2][3].