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

Abstract

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.

Conformationally Constrained Sialyl Analogues as New Potential Binders of h‐CD22

“…Based on the structure of the previously synthesized sialo‐derivative 1 (Figure 1a), [18–20] the synthesis of 2 has been conceived. The sialo‐derivative 2 (Figure 1a), having a similar scaffold than 1 but bearing a biphenyl substituent at position 9, was synthetized based on the observation that a similar sialo‐analogue increased the bound potency and selectivity for CD22 [21] …”

“…Overall, our structural and affinity data showed that the sialyl derivative 1 can strongly interact with h‐CD22; thus, a class of related compounds may be designed as promising candidate for glycoimmunotherapy targeting CD22. Furthermore, the functionalization and characterization of suitable nanomaterials coated with 1 ‐like ligands may lead to interesting therapeutic applications, for example to efficiently probe the cell surfaces [13–33] …”

“…From the structural viewpoint, the synthetic compound is a constrained tricyclic glycoside, that retains the α‐ O ‐glycosidic linkage at the Gal moiety and in which the terminal lactam ring mimics the Thr residue of the Tn/STn natural antigens. The Sialyl TnThr analogue belongs to a class of compounds exhibiting interesting inhibitory activity also toward other biological targets [19–20] …”

“…The Sialyl TnThr analogue belongs to a class of compounds exhibiting interesting inhibitory activity also toward other biological targets. [19][20] With the believe that the rigid galactoside moiety would affect the binding specificity of CD22, here we report the description of the molecular recognition by human CD22 of the Sialyl-TnThr analogue and of a newly synthesized derivative, with the aim to identify novel ligands with therapeutic and diagnostic potential. The binding mode of such sialylated analogues was depicted by using NMR, fluorescence, Surface Plasmon Resonance (SPR), and molecular modelling techniques.…”

Immunological characterization of a rigid α-Tn mimetic on murine iNKT and human NK cells

“…On the basis of these evidences, the aim of the present study was to investigate the activity of the fully synthetic antigen 1 [37,38] (Fig. 1) on iNKT and NK cell activation.…”