Cell-surface α2,3-linked sialic acid glycoconjugates (α2,3-Sia)

Cell-surface glycoconjugates bearing terminal α2,3-linked sialic acid are carbohydrate structures where N-acetylneuraminic acid is attached to a subterminal sugar via an alpha 2,3-glycosidic bond (Varki et al., 2017). These glycans serve as critical host cell receptors for various pathogens, most notably avian influenza viruses (e.g., H5N1), which preferentially bind to α2,3-linkages over the α2,6-linkages preferred by human-adapted strains (Shinya et al., 2006). In humans, these receptors are primarily localized in the lower respiratory tract and the conjunctiva, influencing the tissue tropism and severity of certain infections (Belisle et al., 2010). Beyond infectious disease, these glycoconjugates are often overexpressed in cancer cells, contributing to immune evasion by engaging inhibitory Siglec receptors on myeloid and lymphoid cells (Läubli & Varki, 2020). Therapeutic interventions include sialidase-based drugs like DAS181, which enzymatically remove these sialic acids to prevent viral entry, and novel glyco-immune checkpoint inhibitors like E-602 designed to desialylate the tumor microenvironment (Palleon Pharmaceuticals, 2023). Additionally, α2,3-linked sialic acids are components of selectin ligands, such as Sialyl-Lewis X, which are essential for leukocyte rolling and recruitment during inflammation.

Other names

Neu5Acα2-3Gal3'-SialyllactoseAvian influenza virus receptorAlpha-2,3-sialylglycanSialyl-Lewis X (terminal component)

The primary mechanism of action involves the enzymatic cleavage of terminal sialic acid residues by sialidases (neuraminidases), which removes the binding site for pathogens or immune-inhibitory receptors. Alternatively, small molecule mimetics or antibodies can competitively block the interaction between the α2,3-linked glycan and its cognate binding partners, such as viral hemagglutinin or selectins.