Interaction between SARS-CoV-2 spike glycoprotein and human angiotensin-converting enzyme 2 receptor (SARS-CoV-2 spike–ACE2 interface)

The interaction between the SARS-CoV-2 spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor is the critical molecular interface enabling virus entry into host cells[1][2][3][4][6]. The spike protein's receptor-binding domain (RBD) attaches with high affinity to the ACE2 receptor on the host cell surface, initiating a cascade of conformational changes leading to membrane fusion and viral internalization[3][4]. This protein–protein interface has emerged as a major therapeutic target in COVID-19, as blocking this interaction prevents viral infection. Therapies in development and in clinical use—including monoclonal antibodies, recombinant soluble ACE2, and peptide inhibitors—act by disrupting or competing with the spike–ACE2 interaction[2][3]. Key residues in the spike RBD form hydrogen bonds and salt bridges with defined regions of the ACE2 N-terminal domain, with evolutionary mutations in viral variants (such as N501Y) increasing affinity or altering antibody sensitivity[4][5]. The interface is of therapeutic importance, but interventions must consider the physiological role of ACE2 and possible viral adaptation[3][4][6].

Other names

SARS-CoV-2 spike–ACE2 protein–protein interfaceSARS-CoV-2 S protein–ACE2 interfaceSpike–ACE2 binding interfaceSARS-CoV-2 S glycoprotein–ACE2 interaction

Inhibition of spike–ACE2 binding (by antibodies, peptides or recombinant proteins)[2][3]; Competitive blockade of the ACE2 binding site on spike protein; Stabilization of spike in a conformation that cannot bind/activate fusion[1][4]