Figure 3.

SARS-CoV-2-mediated membrane fusion and its inhibition. (A) Surface and cartoon representation of the three-dimensional structures of full-length ACE2, B^oAT1 and SARS-CoV-2 spike proteins. The left panel is a composite of the cryo-electron microscopy structure of a full-length ACE2 in complex with B^oAT1 (PDB code: 6m17) and the structure of the trimer SARS-CoV-2 spike protein ectodomain in open form (PDB code: 6VYB). The S1 segment of the spike protein, S, bind to its receptors on host cells. This leads to the insertion of the fusion peptide into the host cell membrane and to the conformational change of the now separate S2 domain of S, resulting in the formation of the six-helix bundle and the close approach of the two membranes. The hydrophobic interactions between the fusion peptide and the transmembrane domains of the S protein leads to membrane destabilization and fusion. The structural rendering in the left panel was carried out using PyMol (https://pymol.org, accessed on 1 December 2021). (B) Inhibition of membrane fusion by various peptides. Red: A peptide that binds to the receptor-binding domain of S1. Green: A peptide that inhibits the interaction between S1 subunits. Orange: An S2 fusion peptide mimic that may inhibit the interaction of the fusion peptide with the target membrane. Purple: A peptide derived from the S2-HR2 region that binds with high affinity to the HR1 region and inhibits the interaction between the S2-HR1 and S2-HR2 domains, thus preventing six-helix bundle formation and membrane fusion. Adapted from Düzgüneş and Konopka [29] (Medical Research Archives 8(9), 1–33, 2020 (https://doi.org/10.18103/mra.v8i9.2244, accessed on 1 December 2021).