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

The SARS-CoV-2 spike glycoprotein – human Angiotensin-converting enzyme 2 (ACE2) interaction is the fundamental gateway for viral entry into host cells (Hoffmann et al., 2020, Cell). The viral spike protein's receptor-binding domain (RBD) specifically targets the extracellular peptidase domain of ACE2, a protein widely expressed in the respiratory tract, heart, and kidneys (Yan et al., 2020, Science). This high-affinity binding event triggers a cascade of conformational changes in the spike protein, leading to the fusion of viral and host membranes and the subsequent release of the viral genome (Wrapp et al., 2020, Science). ACE2 itself is a critical enzyme in the renin-angiotensin system, responsible for converting Angiotensin II into the vasodilatory peptide Angiotensin (1-7) (UniProt Q9BYF1). Because this interaction is mandatory for infection, it has been the primary focus for the development of neutralizing monoclonal antibodies, such as Bamlanivimab and Sotrovimab, which block the RBD (FDA, 2022). Additionally, recombinant soluble ACE2 (e.g., APN01) has been explored as a decoy to intercept the virus before it can bind to cellular receptors. A major challenge in targeting this interaction is the rapid evolution of the SARS-CoV-2 virus, where mutations in the RBD can significantly reduce the binding affinity of therapeutic antibodies, leading to viral escape (Lan et al., 2020, Nature).

Other names

Spike-ACE2 interactionSARS-CoV-2 S-ACE2 bindingRBD-ACE2 interactionSARS-CoV-2 entry complex

Competitive inhibition of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein from interacting with the host ACE2 receptor, thereby preventing viral attachment and subsequent membrane fusion.