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

The SARS-CoV-2 Spike–Angiotensin-converting enzyme 2 (ACE2) protein–protein interface is the critical molecular gateway for the entry of the SARS-CoV-2 virus into human host cells. The viral Spike protein, specifically its receptor-binding domain (RBD), recognizes and binds with high affinity to the extracellular peptidase domain of the human ACE2 receptor (UniProt Q9BYF1, P0DTC2). This binding event triggers a conformational change in the Spike protein, facilitating membrane fusion and the subsequent release of the viral genome into the cytoplasm (Lan et al., Nature 2020). Because this interaction is essential for infection, it has become a primary target for the development of neutralizing monoclonal antibodies and small-molecule inhibitors (NIH COVID-19 Treatment Guidelines). Therapeutic strategies aimed at this interface seek to block the physical contact between the RBD and ACE2, thereby preventing viral attachment and entry (Taylor et al., Nature Reviews Genetics 2021). However, the rapid evolution of the virus has led to the emergence of variants with mutations in the RBD that can reduce the efficacy of certain interface-targeting drugs (Harvey et al., Nature Reviews Microbiology 2021).

Other names

SARS-CoV-2 S-ACE2 interfaceSpike-RBD–ACE2 complexS-protein–ACE2 interfaceSARS-CoV-2 receptor binding interfaceSpike-ACE2 interaction site

Competitive inhibition of the protein-protein interaction between the SARS-CoV-2 Spike receptor-binding domain (RBD) and the human ACE2 receptor, thereby blocking viral attachment and subsequent host cell entry.