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

The SARS-CoV-2 spike protein–Angiotensin-converting enzyme 2 (ACE2) interaction is the primary mechanism by which the SARS-CoV-2 virus initiates infection in human hosts (UniProt: P0DTC2, Q9BYF1). The viral spike (S) protein, specifically its receptor-binding domain (RBD), recognizes and binds with high affinity to the extracellular peptidase domain of the host cell surface protein ACE2 (Nature: 10.1038/s41586-020-2179-y). This binding event triggers a conformational change in the spike protein, often facilitated by host proteases like TMPRSS2, leading to viral-host membrane fusion or endocytosis (Science: 10.1126/science.abb2762). Because this interaction is essential for viral entry, it has become a central target for therapeutic intervention, including monoclonal antibodies and soluble ACE2 decoys. Drugs targeting this interaction aim to neutralize the virus by preventing it from docking onto host cells, thereby reducing viral load and preventing the progression of COVID-19. However, the rapid evolution of the spike protein in variants of concern poses a significant challenge, as mutations can reduce the binding affinity of existing therapeutic antibodies. Additionally, while ACE2 is the viral receptor, its physiological role in the renin-angiotensin system must be considered when designing inhibitors to avoid systemic side effects.

Other names

SARS-CoV-2 S-ACE2 bindingSpike-ACE2 complexSARS-CoV-2 entry receptor interactionS-ACE2 PPI

Neutralizing monoclonal antibodies and soluble ACE2 decoys bind to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein or the ACE2 receptor, competitively inhibiting their interaction and preventing viral entry into host cells (PubMed: 32225175, 32142651).