Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands

Area of Science:

• Medicinal Chemistry
• Carbohydrate Chemistry
• Structural Biology

Background:

• Galectins are a family of beta-galactoside-binding proteins implicated in various biological processes.
• Galectin-1 (Gal-1) is a key target for therapeutic intervention due to its roles in immune modulation and cancer progression.
• Developing selective Gal-1 inhibitors is crucial to minimize off-target effects.

Purpose of the Study:

• To synthesize and evaluate novel triazole-thiogalactosides and triazole-thiodigalactosides as potential Gal-1 inhibitors.
• To investigate the structure-activity relationships (SAR) of five-membered heterocycles at the C-4 triazole position for Gal-1 binding.
• To elucidate the binding mode of potent inhibitors using X-ray crystallography.

Main Methods:

• Synthesis of a series of 3-triazole-thiogalactosides and 3,3'-triazole-thiodigalactosides.
• In vitro binding assays to determine affinity and selectivity for Gal-1 over Gal-3.
• X-ray crystallography to determine the co-crystal structure of Gal-1 with a selected inhibitor.

Main Results:

• Compounds with five-membered heterocycles demonstrated increased affinity and selectivity for Gal-1.
• Thien-3-yltriazole and thiazol-2-yltriazole substituted thiodigalactosides exhibited single-digit nM Gal-1 affinity and ~10-fold selectivity.
• X-ray crystallography revealed detailed interactions of a thiophene moiety within the Gal-1 binding pocket, including contacts with Val31, Ser29, Gly124, and Asp123.

Conclusions:

• Steric and electronic optimization of five-membered aromatic heterocycles is key for high-affinity Gal-1 inhibition.
• The identified inhibitors represent promising leads for developing selective Gal-1 therapeutics.
• Structural insights guide further design of potent and selective galectin inhibitors.