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

Abstract

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.

Multivalent 9-O-Acetylated-sialic acid glycoclusters as potent inhibitors for SARS-CoV-2 infection

“…A very recent study revealed that the S protein on SARS-CoV-2 recognizes oligosaccharide containing SAs, with a strong preference for monosialylated gangliosides 12 . Another study supplied a first experimental demonstration of the presence of a α2,3- and α2,6- sialyl N -acetyllactosamine binding site in the NTD of the S1 19 . Here we will focus on 9- O -acetylated-SA (9-AcSA) (Fig.…”

The Glycan-Binding Trait of the Sarbecovirus Spike N-Terminal Domain Reveals an Evolutionary Footprint

“…These results imply that the topology around the H69, Q183, and S247 sites in sarbecovirus spike may play important roles in binding with saccharides. During the preparation of the manuscript, an NMR study demonstrated that the NTD of SARS-CoV-2 spike binds exogenous (α2,3)/(α2,6)-Neu5Ac linked to N -acetyllactosamine, and the galactose moieties display additional contributions for the binding ( 18 ). However, in our study, we found neuraminidase cleavage would not abolish the binding of SARS-CoV-2 and other sarbecovirus S-NTDs to BSM.…”

“…The sialic acid-binding function in transmissible gastroenteritis virus (TGEV) has been suggested to influence viral pathogenicity ( 14 – 16 ), and computational modeling suggests sialic acid binding in SARS-CoV-2 spike may be an immune evasion mechanism ( 17 ). Recent studies also propose that sialic acid or 9- O -Ac sialic acid of glycoproteins and glycolipids might be served as the host factor for SARS-CoV-2 infection ( 18 – 22 ). However, the functional analysis of this phenotype was not fully assessed in cell culture or animal models, leaving the biological impact unknown.…”

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

“…There are reports that the spike protein can recognize structures with sialic acid, as shown in a study where saturation transfer difference nuclear magnetic resonance (STD NMR) was used revealing that the N-terminal domain is capable of interacting with α2,3 sialyl N-acetyllactosamine and α2,6 sialyl N-acetyllactosamine trisaccharides, with preference when the sialic acid is bound by the α2,3 bond [ 92 ]. In another study, it was observed that protein S binds sialylated gangliosides with a similar affinity with which it recognizes HS.…”