Angiotensin-converting enzyme 2–SARS-CoV-2 spike protein interaction interface (ACE2–SARS-CoV-2 S interface)

The ACE2–SARS-CoV-2 spike protein interaction interface is the primary gateway for the entry of the SARS-CoV-2 virus into human host cells. This interface is formed by the binding of the receptor-binding domain (RBD) of the viral spike (S) glycoprotein to the extracellular peptidase domain of the human angiotensin-converting enzyme 2 (ACE2) receptor (Source: Nature, PubMed: 32132184). This high-affinity protein-protein interaction triggers a conformational change in the spike protein, facilitating viral-host membrane fusion or endosomal entry. Because this interaction is essential for viral infectivity, it has become a focal point for therapeutic intervention, including the development of neutralizing monoclonal antibodies, soluble ACE2 decoys, and small-molecule inhibitors (Source: Science, PubMed: 32208330). Disrupting this interface effectively prevents the virus from colonizing respiratory, cardiovascular, and renal tissues where ACE2 is highly expressed. However, the rapid evolution of the virus leads to mutations within the RBD that can increase binding affinity or allow the virus to evade existing therapeutic antibodies, presenting a significant challenge for long-term drug efficacy (Source: Cell, PubMed: 33581021).

Other names

ACE2-RBD interfaceSARS-CoV-2 spike receptor-binding domain-ACE2 complexSpike-ACE2 PPISARS-CoV-2 entry receptor interface

Drugs targeting this interface typically act as entry inhibitors by sterically hindering the binding of the SARS-CoV-2 spike protein receptor-binding domain (RBD) to the host cell receptor ACE2, thereby preventing viral attachment and subsequent membrane fusion or endocytosis (Source: NIH, PubMed: 32225175).