Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study

Abstract

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The “EPN” motif, “NDD” motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.

The Effect of Select SARS-CoV-2 N-Linked Glycan and Variant of Concern Spike Protein Mutations on C-Type Lectin-Receptor-Mediated Infection

“…At this point the differences in trans-infection propensity can be explained by a multitude of factors, ranging from viral instability, to virion capture by other 3t3 cell surface receptors, to DC-SIGN binding to SARS-CoV-2 spike glycans with different binding pockets [ 71 ]. Thus, it was necessary to verify that SARS-CoV-2 spike glycan recognition by DC-SIGN was the causative factor in mediating trans-infection.…”

“…For the purposes of our assessment, we considered a viable “cold spot” to be a glycan cluster variant that exhibits infectivity two orders of magnitude lower than the wild-type virus. This is based on existing work that shows that SARS-CoV-2 can mutate to break through prophylactics and antibodies that attenuate infectivity by 1 to 1.5 orders of magnitude [ 5 , 15 , 20 , 71 , 72 ]. Thus, we posit an epitope site that reduces viral infectivity by more than two orders of magnitude to be under sufficiently strong evolutionary pressure to not mutate.…”

“…While this provides some explanation of why removal of N234 does not impair SARS-CoV-2 pseudoviral trans-infection, it does not explain the increased propensity of the SARS-CoV-2 spike for infection. At this point the differences in trans-infection propensity can be explained by a multitude of factors, ranging from viral instability, to virion capture by other 3t3 cell surface receptors, to DC-SIGN binding to SARS-CoV-2 spike glycans with different binding pockets [71]. Thus, it was necessary to verify that SARS-CoV-2 spike glycan recognition by DC-SIGN was the causative factor in mediating trans-infection.…”