The SARS‐CoV‐2 Spike Glycoprotein Directly Binds Exogeneous Sialic Acids: A NMR View

The interaction of the SARS CoV2 spike glycoprotein with two sialic acid‐containing trisaccharides (α2,3 and α2,6 sialyl N‐acetyllactosamine) has been demonstrated by NMR. The NMR‐based distinction between the signals of those sialic acids in the glycans covalently attached to the spike protein and those belonging to the exogenous α2,3 and α2,6 sialyl N‐acetyllactosamine ligands has been achieved by synthesizing uniformly 13C‐labelled trisaccharides at the sialic acid and galactose moieties. STD‐1H,13C‐HSQC NMR experiments elegantly demonstrate the direct interaction of the sialic acid residues of both trisaccharides with additional participation of the galactose moieties, especially for the α2,3‐linked analogue. Additional experiments with the spike protein in the presence of a specific antibody for the N‐terminal domain and with the isolated receptor binding and N‐terminal domains of the spike protein unambiguously show that the sialic acid binding site is located at the N‐terminal domain. NMR experiments using 13C‐labelled sialyl‐containing trisaccharides unequivocally demonstrate that the N‐terminal domain of the Spike (S) SARS CoV‐2 glycoprotein directly binds sialic acid residues, highlighting the possibility of additional cellular receptor loci for the viral S protein at our cells.