GalNAc Conjugate-Based Delivery Systems

Delivering oligonucleotide therapeutics to specific target sites is a big hurdle limiting their therapeutic utility. Studies have shown that conjugation is an important way to address this limitation. At present, the N-acetylgalactosamine (GalNAc)-conjugation strategy has emerged as a powerful tool to deliver oligonucleotide therapeutics to the liver. Within five years of this discovery, more than twenty-five GalNAc-oligonucleotide conjugates have entered clinical trials to treat liver diseases, suggesting the immense promise this holds. In November 2019, the first GalNAc-conjugated siRNA drug, Givosiran (Givlaari) was approved for the treatment of acute hepatic porphyria (AHP).

GalNAc-Oligonucleotide Conjugates: Mechanism of Liver-Specific Delivery

GalNAc-oligonucleotide conjugates can specifically deliver oligonucleotide therapeutics to hepatocytes inside the liver. This hepatocyte-specific targeting is mediated by a sialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes. In addition to glycoproteins, ASGPR also has high avidity for trivalent GalNAc-oligonucleotide conjugates. ASGPR-mediated endocytosis results in the engulfment of trivalent GalNAc-oligonucleotide conjugates in hepatocytes.

Synthetic Approaches of GalNAc-Oligonucleotide Conjugates

Alfa Chemistry has the ability to synthesize tri-antennary GalNAc and linear polyvalent GalNAc for our customers through two synthetic strategies.

• The first strategy is to pre-assemble a tri-antennary GalNAc ligand on the solid-support (Figure 1)^[1].

Figure 1. Synthetic strategy for GalNAc-oligonucleotide conjugates starting from a pre-assembled tri-antennary GalNAc ligand on solid-support.

• Another strategy is based on multiple bindings of a monomeric GalNAc phosphoramidite during solid-phase oligonucleotide synthesis (Figure 2)^[1]. This strategy based on monomeric GalNAc phosphoramidite allows more flexibility in terms of design, valency and synthesis of GalNAc ligands for oligonucleotides.

Figure 2. Synthetic strategy for linear polyvalent (toothbrush) GalNAc-oligonucleotide conjugates starting from a monomeric GalNAc phosphoramidite.

How We Do?

Alfa Chemistry is proficient in the drug delivery technology of oligonucleotide therapeutics and provides solutions to improve the delivery efficiency and security of oligonucleotide therapeutics. You can also contact us directly to customize GalNAc-oligonucleotide conjugates to speed up your project.

Our products and services are for research use only and cannot be used for any clinical purposes.

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