Toward Glycomimetic Immunomodulators: A Synthetic Dissection of <i>Phocaeicola vulgatus</i> Core Oligosaccharides and Their Recognition by DC-SIGN

Gut microbiota play a pivotal role in maintaining immune homeostasis, with <i>Phocaeicola vulgatus</i> emerging as a key commensal bacterium modulating host inflammatory responses. Central to this immunomodulatory effect is its lipopolysaccharide (LPS), whose core oligosaccharide region has been implicated in selective recognition by dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). Here, we present the efficient synthesis of a diverse set of oligosaccharide fragments from the <i>P. vulgatus</i> LPS core, providing a molecular toolkit to investigate their recognition by DC-SIGN. This novel synthetic approach enabled the generation of structurally well-defined glycans, which were further characterized by using a multidisciplinary strategy combining NMR spectroscopy and computational studies. Ligand-based NMR and molecular simulations provided key insights into the structural features driving DC-SIGN binding, highlighting the role of specific glycan motifs. Given that these synthetic epitopes mimic bacterial glycan signatures, they offer a valuable platform for broader screening studies aimed at uncovering novel lectin-glycan interactions across different microbial species. This approach opens new avenues for exploring the intricate molecular basis of bacterial glycan recognition, expanding our understanding of host-microbe interactions, and driving the design of glycomimetic probes for immune modulation.