Developing Galectin-3-Targeted Therapeutics in Diseases: Three Distinct Galectin-3 Segments for Targeting

The β-galactoside-binding protein galectin-3 is currently a hotly pursued therapeutic target in cancer, inflammation and fibrosis-associated diseases due to its multi-mode actions and broad impact on the pathogenesis and progress of the diseases. Various natures of galectin-3 inhibitors have been developed and investigated, and several have shown promising results in early-phase clinical trials. All these galectin-3 antagonists were designed to target the canonical carbohydrate-binding site, the S-face, of the galectin-3 carbohydrate recognition domain (CRD). This review discussed the current galectin-3 antagonists and explored their modes of actions, focusing particularly on their targeting regions on galectin-3. It discussed the tri-modular structure of galectin-3 and the roles of different segments in galectin-3 actions. It proposed that, in addition to the canonical carbohydrate-binding sites on the S-face, the non-canonical carbohydrate-binding interface, the F-face of the galectin-3 CRD as well as its flexible N-terminal domain are also targetable in the design of galectin-3-targeted therapeutics. Given the high degree of structural similarities of CRDs among galectin family members but unique nature of galectin-3 N-terminus, antagonists developed against the N-terminal domain of galectin-3 can potentially offer greater target specificity by avoiding cross-reactivity with other galectin members. Antagonists that can interact with more than one segment of galectin-3, or a combination of antagonists against different galectin-3 segments, may potentially provide improved efficacy and therapeutic effectiveness for treatment of galectin-3-mediated pathologies and diseases.