Linear triazole‐linked pseudo oligogalactosides as scaffolds for galectin inhibitor development

Abstract

Galectins play key roles in numerous biological processes. Their mode of action depends on their localization which can be extracellular, cytoplasmic, or nuclear and is partly mediated through interactions with β‐galactose containing glycans. Galectins have emerged as novel therapeutic targets notably for the treatment of inflammatory disorders and cancers. This has stimulated the design of carbohydrate‐based inhibitors targeting the carbohydrate recognition domains (CRDs) of the galectins. Pursuing this approach, we reasoned that linear oligogalactosides obtained by straightforward iterative click chemistry could mimic poly‐lactosamine motifs expressed at eukaryote cell surfaces which the extracellular form of galectin‐3, a prominent member of the galectin family, specifically recognizes. Affinities toward galectin‐3 consistently increased with the length of the representative oligogalactosides but without reaching that of oligo‐lactosamines. Elucidation of the X‐ray crystal structures of the galectin‐3 CRD in complex with a synthesized di‐ and tri‐galactoside confirmed that the compounds bind within the carbohydrate‐binding site. The atomic structures revealed that binding interactions mainly occur with the galactose moiety at the non‐reducing end, primarily with subsites C and D of the CRD, differing from oligo‐lactosamine which bind more consistently across the whole groove formed by the five subsites (A‐E) of the galectin‐3 CRD.

Investigation of the Molecular Details of the Interactions of Selenoglycosides and Human Galectin-3

“…The C4-OH participates in hydrogen bonding with His158, Asn160, Arg162 and the water molecule W3 , whilst the C3-OH interacts with two water molecules ( W2 and W3 ). These interactions are consistent with those in the structures of galectin-3 CRD with bound galactose-based derivatives [ 41 , 42 , 43 ].…”

Therapeutic Mechanism and Key Active Ingredients of Shenfu Injection in Sepsis: A Network Pharmacology and Molecular Docking Approach

“…e molecular structure of the core targets in the PDB format was obtained from the RCSB PDB database (https://www.rcsb.org/), where the screening criteria for PDB crystal structures were determined according to the resolution of the protein and whether they have ligands. erefore, we selected IL2 (PDB ID : 1M48) [35], BCHE (PDB ID : 6EQP) [36], AKT1 (PDB ID : 3OS5) [37], and LGALS3 (PDB ID : 6Q17) [38] in the RCSB PDB database for further processing. And, we used PyMol to complete the ligand separation of protein, the removal of water molecules, and the addition of hydrogen atoms.…”

Design and synthesis of novel 3-triazolyl-1-thiogalactosides as galectin-1, -3 and -8 inhibitors

“…30 Many other galectin inhibitors were recently reported. [31][32][33][34] To explore chemical space in the subsites A and B and to investigate possible selectivity between galectin-1, -3, and -8, we assembled a collection of differently substituted phenols that can be attached via a triazole ring to C3 of galactose. The phenols were varied with respect to both the chemical nature of the substituents and the substitution pattern to efficiently explore the subsites A and B.…”