Lectin‐Based Drug Design: Combined Strategy to Identify Lead Compounds using STD NMR Spectroscopy, Solid‐Phase Assays and Cell Binding for a Plant Toxin Model

Abstract

The growing awareness of the sugar code--i.e. the biological functionality of glycans--is leading to increased interest in lectins as drug targets. The aim of this study was to establish a strategic combination of screening procedures with increased biorelevance. As a model, we used a potent plant toxin (viscumin) and lactosides synthetically modified at the C6/C6' positions and the reducing end aglycan. Changes in the saturation transfer difference (STD) in NMR spectroscopy, applied in inhibition assays, yielded evidence for ligand activity and affinity differences. Inhibitory potency was confirmed by the blocking of lectin binding to a glycoprotein-bearing matrix. In cell-based assays, iodo/azido-substituted lactose derivatives were comparatively active. Interestingly, cell-type dependence was observed, indicating the potential of synthetic carbohydrate derivative to interact with lectins in a cell-type (glycan profile)-specific manner. These results are relevant to research into human lectins, glycosciences, and beyond.

Inhibitory potential of chemical substitutions at bioinspired sites of β-d-galactopyranose on neoglycoprotein/cell surface binding of two classes of medically relevant lectins

“…The contact area in the plant toxin for an anomeric extension is thus rather limited, in accord with the mapping of contacts via saturation transfer difference NMR spectroscopy, and the synthetic core modifications did not appear to reach the level of activity of the natural a1,3-linked digalactoside. 12,25,45,46 The Lewis-type trisaccharides were not active, corroborating previous chemical mapping of the relative importance of hydroxyl groups with methyl b-lactoside analogues. 17,47 An anomeric extension beyond lactose showed slight improvements for three of four galectins, here the chimera-type galectin-3 and the two tandem-repeat-type galectins-8 and -9 (Table 1, Fig.…”

Gold‐Loaded Carbon Nanoparticles from Poly(vinyl alcohol)‐b‐poly(acrylonitrile) Non‐Shell‐Cross‐Linked Micelles

“…for galectins‐3 and ‐438, 75–77, or with galactoside libraries differing in the structure of the aglyconic substitution, e.g. between the plant toxin and galectins78, 79, will be helpful to optimize inhibitory potency and interprotein selectivity. Based on the presented results this approach using cyclic neoglycopeptides as scaffold appears to hold promise also for the design of inhibitors against other clinically relevant lectins, e.g.…”

Investigating Protein–Ligand Interactions by Solution Nuclear Magnetic Resonance Spectroscopy

“…Largest signal intensity changes can be found for protons that are in close proximity to their interacting protein. The knowledge about the epitope of the ligand is the starting point for designing and optimizing new drugs . In addition, STD NMR has also been applied to characterize the interactions between ligands in context of membrane protein, living cells, viruses and microtubule assemblies …”