Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions

Area of Science:

• Glycoscience
• Drug Delivery
• Molecular Recognition

Background:

• Cell surface protein-carbohydrate interactions are crucial for biological processes like viral entry and nutrient uptake.
• Multivalent interactions, where multiple ligands bind to receptors, enhance binding affinity and specificity.
• Targeted drug delivery using multivalent ligands offers potential for precise therapeutic interventions.

Purpose of the Study:

• To review the historical development of N-acetylgalactosamine (GalNAc) targeting for drug delivery.
• To highlight the success of Givosiran as a clinical example of carbohydrate-mediated therapeutics.
• To explore future opportunities for GalNAc-targeted delivery systems.

Main Methods:

• Review of academic literature and pharmaceutical development in multivalent glycoscience.
• Analysis of the mechanism of GalNAc ligand uptake via the asialoglycoprotein receptor (ASGP-R).
• Historical tracing of 'cluster glycosides' and their evolution.

Main Results:

• Givosiran, a small interfering ribonucleic acid (siRNA) conjugated to a trivalent GalNAc ligand, is the first clinically approved carbohydrate-mediated drug delivery system.
• The GalNAc ligand facilitates efficient uptake by the asialoglycoprotein receptor (ASGP-R) on hepatocytes.
• Early academic research on synthetic multivalent ligands for ASGP-R laid the foundation for current technologies.

Conclusions:

• GalNAc targeting represents a successful strategy for liver-directed drug delivery.
• The principles of multivalent binding are key to achieving high affinity and specificity.
• Further applications of GalNAc-targeted delivery technologies are anticipated based on this established success.