Glycomimetic ligands for the human asialoglycoprotein receptor

Area of Science:

• Biochemistry
• Drug Delivery
• Hepatology

Background:

• The asialoglycoprotein receptor (ASGPR) is a hepatocyte-expressed receptor crucial for galactose-containing ligand binding.
• Native ASGPR substrates exhibit low binding affinity, necessitating more potent ligands for effective hepatic delivery.

Purpose of the Study:

• To synthesize and evaluate novel galactosyl analogues with enhanced affinity for the ASGPR.
• To explore modifications at various positions of the galactosyl moiety for improved ligand design.

Main Methods:

• Synthesis of diverse galactosyl analogues with substitutions at anomeric, C2-, C5-, and C6-positions.
• Assessment of binding affinity of synthesized analogues to the ASGPR.

Main Results:

• Several trifluoromethylacetamide derivatives demonstrated significantly increased binding affinity.
• New ligands achieved affinities comparable to or exceeding N-acetylgalactosamine.
• Modifications on either side of the C3,C4-diol were well-tolerated, aligning with shallow binding pocket models.

Conclusions:

• The galactosyl pyranose motif is amenable to functionalization for enhanced ASGPR targeting.
• Developed ligands offer low-micromolar or better affinity, suitable for therapeutic payload attachment.
• These findings pave the way for advanced hepatic drug delivery systems.