Human Galectin-3 Selective and High Affinity Inhibitors. Present State and Future Perspectives

Abstract

Over the last decade an increasing number of studies have been published reporting on the inhibitory potency or selectivity that several types of ligands show against human galectin-3 (hGal-3). The reason for this interest lies in the many important roles galectins play both in intra and extra-cellular functions. Among galectins, galectin-3 stands out because it is the only known member of its subfamily in mammals, is small and monomeric but capable of aggregating, and is known to be involved in a large number of disease processes, from cancer to heart failure. These characteristics and roles make hGal-3 an ideal target for drugs. Since it binds β-galactosides, like the rest of the galectin family of proteins, the search and design of potent and at the same time selective inhibitors for it is not an easy task. Herein we discuss the chemical features of the most potent inhibitors described so far, as well as the structural basis of their exhibited selectivity, in order to shed light on the rational design of drugs against this target.

Functions of Galectin-3 and Its Role in Fibrotic Diseases

“…First, in-depth research into the functional network of Gal-3 associated with the mitogen-activated protein kinase/ERK1/2 pathway, caspase activation, b-catenin/GSK-3b signaling, EMT process, and TGF-b/Smads signaling will help clarify the pathogenesis of organ fibrosis. Second, the compounds that have hydrophilic substituent at the taloside O2 position may enhance specificity for binding human Gal-3, and further research involving these selective and high-affinity Gal-3 inhibitors may be an effective route to attenuating fibrosis (Téllez-Sanz et al, 2013). Thirdly, it is pivotal to determine whether the inhibitors used should target Gal-3 in extra-or intracellular space in different types of fibrosis.…”

Multivalent scaffolds induce galectin-3 aggregation into nanoparticles

“…Binding affinities have been reported for a series of carbohydrate-based ligands to galectin-3, which binds to lactose significantly better than to galactose or to N -acetylgalactosamine but does not bind to mannose [22–24]. Both the glycan ligand and the topological display on the cell surface are required for high affinity, selective binding of galectins, as demonstrated in galectin binding studies with neuroblastoma cells [25].…”

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

“…In addition to the review presented here, other recent reviews are informative although focus on narrower aspects and consequently are overall less comprehensive. [42,43,132,133] Galactose-Based Inhibitors Despite galactose being the essential binding moiety for galectins, the actual binding affinity for galactose is only ,3-10 mM while disaccharides such as lactose show affinities in the range of 90-500 mM. [49] However, because saccharidebased inhibitors are hydrophilic, glycolytically unstable, and are not able to effectively cross the plasma membrane, the glucose (Glc) of lactose was replaced by thio-linked hydrophobic, aromatic groups and the resulting compounds were able to achieve 140-170 mM affinity, about the same as that of disaccharide lactosides, against galectin-7 (Fig.…”

“…[42,43] The ability of galectins to form dimers and oligomers have been exploited by multivalent inhibitors [44] and highly glycosylated natural products. [45,46] In addition, several peptide-based inhibitors and peptidomimetics have been found that have certain levels of efficacy.…”