When conjugated to oligonucleotide drugs, Triantennary N-Acetylgalactosamine (GalNAc) enhances their specific delivery to targets in liver cells. Already, the FDA has approved several GalNAc-conjugated oligonucleotides for clinical use.
The ligand of the asialoglycoprotein receptor (ASGPR), triantennary N-acetylgalactosamine (tri-GalNAc), when conjugated to oligonucleotides, improves their cellular uptake and tissue-specific delivery. ASGPR binds glycoproteins with terminal galactose residues in liver cells and removes targeted glycoproteins from circulation. The half-life of therapeutic GalNAc-RNAi drugs is relatively long, allowing monthly to half-yearly dosing regiments.
The conjugation of siRNAs to multivalent GalNAc linkers enhances their delivery and gene silencing in liver cells. GalNAc linkers attached to the 3'-end of siRNA sense strands allow delivery into cells without additional delivery reagents. GalNac-conjugates oligonucleotides exhibit improved tissue-specific delivery for antisense oligonucleotides (ASOs) and siRNAs.
The GalNAc technology, also known as the "GalNAc siRNA platform" enhances the unfavorable pharmacokinetics of oligonucleotide therapeutics for hepatic drug targets. The half-life of GalNAc-RNAi drugs' therapeutics is quite long, resulting in monthly to half-yearly dosing regiments. Furthermore, N-acetylgalactosamine (GalNAc) ligands improve oligonucleotides' cellular uptake and tissue-specific delivery. Read on ....
siRNAs silencing disease-causing genes in hepatocytes utilize the triantennary GalNAc linker targeting the asialoglycoprotein receptor (ASGPR). Conjugated GalNAc-siRNAs enable an efficient way of increasing siRNA target organ accumulation and facilitating cellular uptake. Natural siRNA needs to be chemically modified to ensure stability in the circulation after parenteral administration. Designing siRNAs using modified nucleic acids improves their metabolic stability, reduces recognition by Toll-like receptors 3 and 7, and increases binding to target mRNA.
Backbone modifications initially developed for antisense oligonucleotide (ASO) therapeutics can also be applied to siRNA therapeutics. Typical modifications include 2′-OMe, 2′-fluoro, and phosphorothiorate linkages.
5΄-phosphate mimics can stabilize the 5΄-end of the guide strand by protecting it from phosphatases and 5΄-to-3΄-exonucleases. For example, the improved stability significantly enhances the efficacy of cholesterol-conjugated siRNAs and the duration of silencing in vivo. 5΄-(E)-vinylphosphonate stabilizes 5΄-phosphate and enables systemic delivery to and silencing in the kidney and heart. Several 5'-phosphate modifications are available for the production of synthetic siRNA conjuagtes. Read on ....
" Bio-Synthesis provides custom synthesized GalNAc-conjugated oligonucleotides including GalNAc-siRNAs.
Bio-Synthesis also provides a full spectrum of high quality custom oligonucleotide modification services including back-bone modifications, conjugation to fatty acids, biotinylation by direct solid-phase chemical synthesis or enzyme-assisted approaches to obtain artificially modified oligonucleotides, such as BNA antisense oligonucleotides, mRNAs or siRNAs, containing a natural or modified backbone, as well as base, sugar and internucleotide linkages.
Bio-Synthesis also provides biotinylated and capped mRNA as well as long circular oligonucleotides".