Structure-Based Design of a Monosaccharide Ligand Targeting Galectin-8

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Galectin-8 regulates bone remodeling and is a target for bone loss diseases.
• Targeting galectin-8 offers a potential therapeutic strategy for bone-related conditions.

Purpose of the Study:

• To design and synthesize a novel ligand targeting the N-terminal domain of galectin-8 (galectin-8N).
• To validate the binding affinity and interactions of the designed ligand with galectin-8N.

Main Methods:

• Molecular dynamics (MD) simulations to predict ligand-protein interactions.
• Synthesis of methyl 3-O-[1-carboxyethyl]-β-d-galactopyranoside (compound 6).
• Isothermal titration calorimetry (ITC) to determine binding affinity.
• X-ray crystallography to elucidate the complex structure.

Main Results:

• Compound 6 was designed to mimic interactions of 3'-O-sialylated lactose (3'-SiaLac) with galectin-8N.
• ITC showed a binding affinity of 32.8 μm for galectin-8N, with no significant binding to galectin-8C.
• Crystal structure confirmed the predicted binding mode and identified key protein-ligand interactions.

Conclusions:

• A rational design approach yielded a monosaccharide-based scaffold (compound 6) that selectively binds galectin-8N.
• This study demonstrates a viable strategy for developing galectin-8 targeted therapeutics for bone loss diseases.