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

The SARS-CoV-2 Spike protein – human ACE2 interaction interface is the primary gateway for the entry of the severe acute respiratory syndrome coronavirus 2 into host cells [1.1.1, 1.5.1]. This interface is formed between the receptor-binding domain (RBD) of the viral Spike (S) protein and the peptidase domain of the human angiotensin-converting enzyme 2 (ACE2) receptor [1.3.1, 1.5.5]. The high-affinity binding (K_d ~1-30 nM) triggers a series of conformational changes in the Spike protein, leading to membrane fusion and the release of the viral genome into the cytoplasm [1.3.2, 1.3.5]. Because this interaction is essential for infection, it has become a central target for therapeutic interventions, including neutralizing monoclonal antibodies, soluble ACE2 decoys, and small-molecule inhibitors [1.2.1, 1.3.1]. Neutralizing antibodies typically bind to the RBD to competitively block ACE2 engagement, while decoy receptors like soluble ACE2 mimic the host receptor to sequester the virus [1.1.1, 1.2.1]. However, the rapid evolution of the virus, particularly mutations within the RBD, poses a significant challenge to the long-term efficacy of these treatments, necessitating the development of broadly neutralizing agents [1.1.2, 1.5.1]. Furthermore, targeting this interface requires careful consideration of the physiological role of ACE2 in the renin-angiotensin system to avoid adverse cardiovascular effects [1.1.1, 1.5.4]. Overall, the Spike-ACE2 interface remains a critical focus for drug discovery and vaccine development in the ongoing effort to manage COVID-19 [1.3.4, 1.4.3].

Other names

SARS-CoV-2 S-ACE2 complexSpike-ACE2 interfaceRBD-ACE2 interfaceACE2-interacting surface (ACE2IS)

Competitive inhibition of the protein-protein interaction (PPI) between the SARS-CoV-2 Spike protein receptor-binding domain (RBD) and the human Angiotensin-converting enzyme 2 (ACE2) receptor, preventing viral attachment and subsequent host cell entry [1.2.1, 1.3.1].