Dissecting the Structure–Activity Relationship of Galectin–Ligand Interactions

Abstract

Galectins are β-galactoside-binding proteins. As carbohydrate-binding proteins, they participate in intracellular trafficking, cell adhesion, and cell–cell signaling. Accumulating evidence indicates that they play a pivotal role in numerous physiological and pathological activities, such as the regulation on cancer progression, inflammation, immune response, and bacterial and viral infections. Galectins have drawn much attention as targets for therapeutic interventions. Several molecules have been developed as galectin inhibitors. In particular, TD139, a thiodigalactoside derivative, is currently examined in clinical trials for the treatment of idiopathic pulmonary fibrosis. Herein, we provide an in-depth review on the development of galectin inhibitors, aiming at the dissection of the structure–activity relationship to demonstrate how inhibitors interact with galectin(s). We especially integrate the structural information established by X-ray crystallography with several biophysical methods to offer, not only in-depth understanding at the molecular level, but also insights to tackle the existing challenges.

Targeting Galectins With Glycomimetics

“…Galectins are involved in a wide range of biological activities, such as homeostasis, apoptosis, and vascular embryogenesis (Chan et al, 2018 ). Their involvement in pathological contexts has been described for inflammation (Brinchmann et al, 2018 ), host-pathogen interaction (Vasta, 2009 ), antibacterial autophagy (Weng et al, 2018 ), and cancer (Liu and Rabinovich, 2005 ; Girotti et al, 2020 ).…”

Galectin-3 as a Therapeutic Target for NSAID-Induced Intestinal Ulcers

“…Indeed, galectin inhibitors, which inhibit Gal3 predominantly and Gal1 partially, have already been shown to be safe and applicable in several disease conditions, clinically and experimentally. Recently, TD139 also known as GB0139 has attracted attention as a highly specific Gal3/Gal1 inhibitor: the affinity of TD139 for Gal3 with K d = 14 nM and for Gal1 with K d = 10 nM, but low for galectins 2, 4, 7, 8, or 9 (41). Currently, TD139 is used in a clinical trial for idiopathic pulmonary fibrosis (IPF).…”

The Structural Biology of Galectin-Ligand Recognition: Current Advances in Modeling Tools, Protein Engineering, and Inhibitor Design

“…Although the ligand exhibits similar binding modes for Gal-1 and Gal-3, a remarkably different conformation is observed in the Gal-7 complex (Figure 8A), involving a disfavourable rotation of one of its 4-fluorophenyl substituents, prompted by the presence of a His residue at position 3 of the S3 strand (near the subsite B), in contrast to the less bulky Val occupying this same position in Gal-1 or the Ala in Gal-3. This difference in the structure offers a simple albeit elegant explanation to the several orders of magnitude in their ITC-determined dissociation constants (Gal-7 K d = 38 μM, Gal-3 K d = 0.068 μM) (Chan et al, 2018).…”