The SARS-CoV-2 spike protein contains a furin cleavage site located in a short loop between antiparallel ß-strands.

ABSTRACT

The furin cleavage site (FCS) of the SARS-CoV-2 spike protein, which connects the S1/S2 junction, is essential for facilitating fusion with host cells. The wild-type (Wt) SARS-CoV-2 spike protein, PDB ID 6yvb, lacks a sequence of amino acid residues, including the FCS that links the S1/S2 junction. For the first time, we demonstrated that a stretch of 14 amino acid residues (677QTNSPRRARSVASQ689) forms an antiparallel ß-sheet and contains the PRRAR sequence in the FCS within a short loop. Upon comparing the loop content of the S1/S2 junction with that of Wt SARS-CoV-2 containing PRRAR in the FCS, we observed a decrease in antiparallel ß-sheet content and an increase in loop content in the B.1.1.7 variant with HRRAR in the FCS. This short loop within an antiparallel ß-sheet can serve as a docking site for various proteases, including TMPRSS2 and α1AT. We conducted a 300-ns simulation of the SARS-CoV-2 receptor binding domain (RBD) using several antibacterial and antiviral ligands commonly used to treat various infections. Our findings indicate that the receptor binding domain (RBD) comprising the receptor binding motif (RBM) utilizes ß6 and a significant portion of the loop to bind with ligands, suggesting its potential for treating SARS-CoV-2 infections.