SARS-CoV-2 Evolved Variants Bind to Sialylated Gangliosides and Are Inhibited by a Tetravalent Sialo-Glycocluster.

Abstract

The altered tropism and infection severity of the evolved SARS-CoV-2 variants indicate engagement of attachment factors other than the ACE2 receptor for the cellular attachment and entry of the virus. In this work, we report the binding of Omicron, Delta, and B.1.1.8 (A2a type) variants to gangliosides (GD1a, GM3, GM1) with terminal sialic acid (SA). The binding kinetics of intact virus particles to these ganglioside-embedded lipid membranes reveal that the affinity of Omicron for GD1a (two SA residues) is the highest, and the lowest affinity is that of B.1.1.8 for GM1 (one SA at the branched chain). Our TIRF imaging data confirm that SA and acetylated SA can inhibit the virus attachment to the bilayers but at millimolar concentration. We evaluated tetravalent glycoclusters, i.e., sialo-porphyrin, galactose-porphyrin, and glucose-porphyrin, as multivalent inhibitors of SARS-CoV-2. Our results show that membrane attachment of the variants is blocked by the micromolar concentration of sialo-porphyrin. Even the glycocluster effectively inhibits cellular infection caused by the variants.