Artificial Glycan Decoys: A Strategy to Inhibit Ebola Virus Infection

Multivalency is a fundamental principle of lectin-glycan recognition, governing both affinity and specificity of carbohydrate-mediated molecular interactions. The human macrophage galactosetype lectin (MGL), a C-type lectin that selectively binds galactose (Gal) and Nacetylgalactosamine (GalNAc) residues, serves as an attachment factor for several enveloped viruses, including Ebola virus (EBOV). Here, we report the rational design and synthesis of GalNAc-based glycans multiantenna that structurally mimic viral surface glycosylation architectures and act as competitive inhibitors of MGL-mediated viral entry. A library of glycoconjugates bearing two, four, or eight Ser(GalNAc) units was chemically synthesized, and their interactions with the carbohydrate recognition domain of MGL (MGL-CRD) were investigated using 1 H, 15 N-HSQC-based NMR titrations and isothermal titration calorimetry (ITC). These studies revealed a pronounced multivalency-dependent increase in affinity and aviditydriven stabilization of the lectin-glycan complex, consistent with the simultaneous engagement of multiple MGL binding sites. Functional inhibition assays employing pseudotyped and wild-type EBOV particles demonstrated that these multiantenna constructs efficiently block MGL-mediated viral entry, achieving submicromolar inhibitory potency. Together, these findings establish GalNAc-based multiantenna glycans as effective chemical decoys that disrupt lectin-mediated viral attachment and highlight multivalency as a powerful molecular design strategy for antiviral intervention.