Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases

Abstract

Galectin-3 (Gal3) is one of the most studied members of the galectin family that mediate various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Since Gal3 is pro-inflammatory, it is involved in many diseases that are associated with chronic inflammation such as cancer, organ fibrosis, and type 2 diabetes. As a multifunctional protein involved in multiple pathways of many diseases, Gal3 has generated significant interest in pharmaceutical industries. As a result, several Gal3-targeting therapeutic drugs are being developed to address unmet medical needs. Based on the PubMed search of Gal3 to date (1987-2023), here, we briefly describe its structure, carbohydrate-binding properties, endogenous ligands, and roles in various diseases. We also discuss its potential antagonists that are currently being investigated clinically or pre-clinically by the public and private companies. The updated knowledge on Gal3 function in various diseases could initiate new clinical or pre-clinical investigations to test therapeutic strategies, and some of these strategies could be successful and recognized as novel therapeutics for unmet medical needs.

Keywords: NASH; cancer; diabetes; fibrosis; galectin-3; inhibitor.

Figure 1

Classification of galectins. Schematic representation of proto-, chimera, and tandem-repeat type galectins. Galectins are numbered according to the order of their discovery.

Figure 2

Structure of Gal3. Schematic representation of nucleotide (cDNA) and protein (primary and tertiary) structures of Gal3. The 3-D model of Gal3 CRD complexed with N-acetyllactosamine (PDB ID: 1KJL) was obtained from the NCBI (https://www.ncbi.nlm.nih.gov/Structure/pdb/1KJL (accessed on 7 November 2022)).

Figure 3

Various functions of Gal3. Schematic representation showing involvement of Gal3 in various diseases.

Figure 4

Role of Gal3 in the promotion of tumor angiogenesis, cancer metastasis, and T-cell apoptosis. (A) Schematic representation of Gal3 mediated tumor cell angiogenesis. (B) Schematic representation of Gal3 mediated tumor-endothelial cell interactions and tumor cell extravasation. (C) Schematic representation of anti-apoptotic function of cytoplasmic Gal3. (D) Schematic representation of Gal3-mediated apoptosis of T-cells. (Adapted from Ref. [21]).

Figure 5

Role of Gal3 in the promotion of organ fibrosis. Schematic representation of Gal3 driven inflammatory pathways leading to organ fibrosis. TGF-β, transforming growth factor-β; PDGF, platelet-derived growth factor; DAMPS, damage-associated molecular patterns. (Adapted from Ref. [128]).

Figure 6

Role of Gal3 in the promotion of insulin resistance in type 2 diabetes. Schematic representation showing macrophage-secreted Gal3 from obese individuals drives insulin resistance and glucose intolerance by directly binding insulin receptor (IR) and antagonizing downstream metabolic responses. (Adapted from Ref. [11]).