SARS-CoV-2 spike receptor-binding domain–Angiotensin-converting enzyme 2 protein–protein interaction (SARS-CoV-2 RBD–hACE2 PPI)

The SARS-CoV-2 spike receptor-binding domain (RBD)–Angiotensin-converting enzyme 2 (hACE2) protein–protein interaction is the critical initial step in the infection cycle of the SARS-CoV-2 virus (PubMed: 32225175). The viral spike (S) protein, specifically the S1 subunit's RBD, binds with high affinity to the extracellular peptidase domain of the human ACE2 receptor, which is widely expressed in the lungs, heart, and kidneys (UniProt: Q9BYF1). This interaction facilitates the docking of the virus onto the host cell membrane, followed by proteolytic cleavage and membrane fusion (Nature: 581, 215–220). As the primary mechanism for viral entry, this PPI is a major therapeutic target for neutralizing monoclonal antibodies, such as Sotrovimab and Bebtelovimab, which competitively bind to the RBD to prevent ACE2 engagement (NIH: COVID-19 Treatment Guidelines). Additionally, soluble ACE2 decoys and small-molecule inhibitors are being explored to disrupt this interface. A significant challenge in targeting this interaction is the emergence of viral variants of concern (VOCs) that harbor mutations in the RBD, potentially leading to immune evasion and reduced drug efficacy (Science: 367, 1260-1263).

Other names

SARS-CoV-2 S-RBD/hACE2 interactionSpike-ACE2 interfaceSARS-CoV-2 entry complexS-RBD:hACE2 complex

Neutralizing monoclonal antibodies and entry inhibitors bind to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein or the extracellular domain of hACE2, sterically hindering the protein-protein interaction and preventing viral attachment and subsequent entry into host cells (PubMed: 32225175).