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

Abstract

Galactose is the key contact site for plant AB-toxins and the human adhesion/growth-regulatory galectins. Natural anomeric extensions and 3'-substitutions enhance its reactivity, thus prompting us to test the potential of respective chemical substitutions of galactose in the quest to develop potent inhibitors. Biochemical screening of a respective glycoside library with 60 substances in a solid-phase assay was followed by examining the compounds' activity to protect cells from lectin binding. By testing 32 anomeric extensions, 18 compounds with additional 3'-substitution, three lactosides and two Lewis-type trisaccharides rather mild effects compared to the common haptenic inhibitor lactose were detected in both assays. When using trivalent glycoclusters marked enhancements with 6- to 8-fold increases were revealed for the toxin and three of four tested galectins. Since the most potent compound and also 3'-substituted thiogalactosides reduced cell growth of a human tumor line at millimolar concentrations, biocompatible substitutions and scaffolds will be required for further developments. The synthesis of suitable glycoclusters, presenting headgroups which exploit differences in ligand selection in interlectin comparison to reduce cross-reactivity, and the documented strategic combination of initial biochemical screening with cell assays are considered instrumental to advance inhibitor design.

Galectin-1-Specific Inhibitors as a New Class of Compounds To Treat HIV-1 Infection

“…Pioneering studies led by Nilsson and colleagues and Giguere and colleagues reported the development of specific galectin inhibitors by using soluble glycans in fluorescence polarization assays (27,51,63,64,73). Other findings also reported that a multimeric or a clustered arrangement of lacto- side derivatives may enhance their affinity for specific galectins (2,29).…”

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

“…A recent review summarises the strategy, limitations, and expectations of a multivalent display of galectin-binding saccharides. [44] Multivalent ligand display approaches utilised thus far have been bi-to tetravalent glycoclusters, [92][93][94][95][96] much larger glycoclusters such as wedge-like and starburst dendrimers that present 8-128 saccharides, [97,98] cyclodextrin-based glycoclusters, [99][100][101][102] calix[n]arene-based glycoclusters, [103][104][105] cyclic neoglycopeptides, [106,107] and cyclophanes and terephthalamides. [108] Consistently, one of three types of assays are reported to evaluate the galectin multivalent inhibitor efficiency: solid-phase competitive inhibition assay between immobilised glycoproteins and galectins, in vitro competitive assay where the inhibitor is competing against the binding of galectins to cell surface receptors, and haemagglutination inhibition assays.…”

Development of a Sensitive Microarray Platform for the Ranking of Galectin Inhibitors: Identification of a Selective Galectin‐3 Inhibitor

“…Lactulose, a galactose‐containing disaccharide, has sometimes been used as an alternative . Switching from di‐ to monosaccharides such as galactose and talose (uniquely differing from galactose by the configuration of the C2 position) was proposed, but until very recently, the observed affinities were usually limited to the millimolar to high micromolar range . To date, most potent galectin inhibitors are thiodigalactoside derivatives (or closely related thioditaloside or selenodigalactoside derivatives), initially introduced as lactosamine/lactose mimics, the C2 symmetry of which considerably simplifies both synthesis and functionalization .…”