Structural Insights into the Binding of Sugar Receptors (Lectins) to a Synthetic Tricyclic Tn Mimetic and Its Glycopeptide Version

Cycloadduct 1 is a conformationally constrained mimetic of the tumor‐associated Tn antigen. It maintains the 4C1 conformation and the α‐O‐glycosidic linkage of the natural epitopes. Due to its tricyclic structure, the anomeric linkage is constrained and its conformation “frozen”. Using saturation transfer difference NMR spectroscopy experiments, epitope mapping for binding by three lectins [i.e., from Erythrina cristagalli (ECL), human macrophages (MGL), and from Helix pomatia (HPA)] was carried out. Striking differences in the epitope viewed from the ligand's perspective were revealed by this comparison. Evidently, the structural change around the C‐2 position has a major impact, if the contact pattern to the ligand is not mostly restricted to galacto configuration with the axial hydroxyl group at C‐4, in combination with C‐3/C‐6. These measurements thus provide insights into actual contacts, which help predict applicability as an inhibitor for distinct lectins, and as an elicitor of specific antibodies. A mimetic of the tumor‐associated Tn antigen (CD175) and its glycopeptide interacts differently with lectins from a plant, a snail, and human macrophages. The conformation of the mimetic and the lectins' binding site topology contribute to the variation. Extrapolations about ligand recognition should thus be considered carefully, even for lectins that share specificity for a given monosaccharide.