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

The SARS-CoV-2 spike–Angiotensin-converting enzyme 2 (ACE2) interaction interface is the critical molecular contact area between the Receptor Binding Domain (RBD) of the viral spike protein and the human ACE2 receptor. This high-affinity protein-protein interaction serves as the primary gateway for viral entry into host cells, initiating the infection process through attachment and subsequent membrane fusion. Structurally, the interface involves specific residues such as Lys417 and N501 on the spike protein that form a network of hydrogen bonds and salt bridges with ACE2 residues like Asp30 and Lys353. Because this interaction is the first step in the viral life cycle, it has become a central target for neutralizing monoclonal antibodies, such as Bamlanivimab and Sotrovimab, as well as decoy receptors like soluble ACE2. However, the interface is a hotspot for mutations, leading to the emergence of variants of concern that can increase viral infectivity or evade existing immune responses. Therapeutic agents targeting this interface aim to block viral attachment while ideally preserving the physiological enzymatic activity of ACE2, which is vital for regulating the renin-angiotensin system. ACE2 impairment can lead to cardiovascular and pulmonary complications, making the selective modulation of this interface a significant therapeutic challenge. Consequently, drug development must account for both the rapid evolution of the viral spike and the host's physiological requirements to ensure efficacy and safety.

Other names

SARS-CoV-2 S-ACE2 complexSpike-ACE2 interfaceRBD-ACE2 interfaceACE2-interacting surfaceACE2ISSpike RBD-ACE2 interface

Inhibition of viral entry by blocking the interaction between the viral spike protein receptor-binding domain (RBD) and the host cell receptor angiotensin-converting enzyme 2 (ACE2).