Because Galectins have an intriguing combination of intracellular and extracellular activities, they have diverse important functions and are involved in many biological processes such as cell growth, cell adhesion, and signaling. In addition, Galectins play a profound role in many diseases, like inflammation, cancer, and fibrosis. Due to these important biology roles and to better understand the mechanism of Galectin’s action in relevant therapies, selective and potent inhibitors for Galectins will be valuable tools to investigate the biological functions of different Galectins. So far, the two Galectins most studied in this regard are Galectin-1 and Galectin-3, which are targets of scientific and pharmaceutical study.
Fig.1 Gal-3 inhibition may disrupt the attachment of SARS-CoV2 S1-NTD to GM1 gangliosides on the cell surface. (Caniglia, et al., 2020)
Most Galectin activities result from binding β-Dgalactopyranoside-containing glycoconjugates. Thus, efforts towards developing Galectin inhibitors focused on inhibiting the CRD of Galectins to compete with the natural ligands. The CRD can be schematically divided into five subsites (A~E in figure 2). Nacetyllactosamine (LacNAc) is a natural ligand fragment for Galectins found in many cell-surface glycoconjugates. The observed hydrogen-bonding pattern of the β-galactoside moiety of LacNAc is crucial for the recognition by Galectins and is probably indispensable for the design of Galectin inhibitors. Therefore, the previous work on Galectin inhibitors focused on modifications at galactose's anomeric carbon, HO-2, or HO-3 to access the less conserved CRD subsites to gain binding affinity and/or selectivity. Researchers have developed a variety of inhibitors targeting galactose lectins, which can be classified into natural polysaccharides, nucleic acids, antibodies, and synthetic small molecule glycans according to their structures.
Fig.2 Illustration of subsites A-E of the Galectin CRD, exemplified with LacNAc (cyan sticks) bound to the CRD of Galectin-3. (Hassan, M., 2022)
Lactose is the best natural sugar ligand for galactose lectin, but due to its high hydrolysis sensitivity and high polarity, small monosaccharide molecules such as β-D-galactosyl methyl glucoside are preferable. The development of small molecule galactose lectin inhibitors is mainly focused on the C(1), C(2), and C(3) positions of galactose, for example, monosubstituted derivatives are mainly modified at the C(1) position to improve the affinity by introducing aromatic (hetero) rings. In addition, the double-substituted derivatives are beneficial to increase the interaction between the compound and galactose lectin, which can improve the affinity more efficiently. The trisubstituted galactose derivatives showed an inferior affinity for Galectin-3 than the bisubstituted thioside derivatives but showed a better affinity for other family members.
Galectin-3 is a unique type of chimeric protein in the Galectin family. Gal-3 has a wide range of regulatory functions that have been implicated in the pathogenesis of many different human diseases, including cancer, inflammation, idiopathic pulmonary fibrosis (IPF), and hepatic fibrosis, and therefore it has attracted significant interest as a potential therapeutic target. Previous studies have shown that thiodisaccharide chemotypes of Galectin-3 inhibitors, although effective, are often unsuitable for conventional oral administration due to their undesirable drug-like properties. The synthesis and evaluation of tetrahydropyran-based thiodisaccharide mimetics provide a new strategy for the development of Galectin-3 inhibitors.
Fig.3 Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent Galectin-3 inhibitors, compound 45 was selected for further in vivo evaluation. (Zhang, et al., 2018)
Carbohydrates play an important role in many biological processes because they are recognition groups for lectins and receptors. The interaction of lectins with carbohydrate ligands has a very weak strength. For glycoproteins and glycolipids, the binding strength may be greatly increased by presenting multiple glycoligands in the glycan cluster. Therefore, multivalent glycoligands have been designed for drug research and anticancer therapy to improve binding affinity and inhibition. The presentation of multivalent carbohydrates is mostly achieved by chemical modification of different scaffolds that define the arrangement and orientation of the glycans. Researchers commonly use serum albumin as a scaffold for the presentation of multivalent sugars for binding to Galectins. It contains multiple lysine residues and can be easily processed by chemical ligation methods.
Fig.4 The multivalent attachment of a TDG derivative using bovine serum albumin (BSA) as the scaffold. (Zhang, et al., 2018)
the creation of a heterobifunctional inhibitor that can bind both metalloproteinases and members of the Galectin protein family at the same time. Matrix metalloproteinases (MMPs) are among of the downstream effectors that a Galectin (Gal) upregulates in disease development, such as MMP-9 by Gal-7 in murine T cell lymphoma cells27 or MMP-3 by Gal-3 in human rheumatoid synovial fibroblasts. Some researchers created a heterobifunctional molecule made up of a water-soluble MMP inhibitor in response to this evidence for a functional relationship between Galectin and an MMP. The idea of designing heterobifunctional inhibitors has lately attracted more attention.
Fig.5 The design of heterobifunctional inhibitors that can block Galectin binding and MMPs both directly and by preventing their Galectin-dependent induction selectively offers a perspective to dissect the roles of lectins and proteolytic enzymes. (Manning, et al., 2022)
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