SARS-CoV-2 spike protein receptor-binding domain–Angiotensin-converting enzyme 2 protein–protein interaction (SARS-CoV-2 S RBD–ACE2 PPI)

The SARS-CoV-2 spike protein receptor-binding domain (RBD)–Angiotensin-converting enzyme 2 (ACE2) protein–protein interaction is the fundamental gateway for the entry of the SARS-CoV-2 virus into human cells (Lan et al., Nature, 2020, PMID: 32225176). The spike protein, located on the viral surface, utilizes its RBD to specifically recognize and bind to the extracellular peptidase domain of ACE2, a membrane-bound enzyme found in various tissues including the lungs, heart, and kidneys (UniProt Q9BYF1; Yan et al., Science, 2020, PMID: 32132184). This binding event triggers a conformational change in the spike protein, facilitating membrane fusion and the release of the viral genome into the host cytoplasm (Hoffmann et al., Cell, 2020, PMID: 32130906). As the primary step in the infection cycle, this interaction is a high-priority therapeutic target for the development of neutralizing monoclonal antibodies and small-molecule inhibitors (Barnes et al., Nature, 2020, PMID: 32822944). Drugs targeting this interface, such as Sotrovimab and Bebtelovimab, aim to block the physical contact between the virus and the host cell, effectively preventing the initiation of COVID-19 (FDA, 2022). However, the rapid evolution of the virus leads to mutations within the RBD that can reduce the binding affinity of existing therapeutics, presenting a significant challenge for long-term efficacy (Harvey et al., Nat Rev Microbiol, 2021, PMID: 34131329).

Other names

SARS-CoV-2 S-ACE2 interactionSpike-ACE2 complexRBD-ACE2 interfaceSARS-CoV-2 receptor-binding domain–ACE2 interactionS-ACE2 PPI

Neutralizing antibodies and entry inhibitors bind to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein or the extracellular domain of the ACE2 receptor to sterically hinder or competitively inhibit their interaction, thereby preventing viral attachment and subsequent entry into the host cell (Barnes et al., Nature, 2020, PMID: 32822944; FDA, 2022).