Metabolically Stable Anomeric Linkages Containing GalNAc-siRNA Conjugates: An Interplay among ASGPR, Glycosidase, and RISC Pathways

被引：19

作者：

Kandasamy, Pachamuthu ^{[1
]}

Mori, Shohei ^{[1
]}

Matsuda, Shigeo ^{[1
]}

Erande, Namrata ^{[1
]}

Datta, Dhrubajyoti ^{[1
]}

Willoughby, Jennifer L. S. ^{[1
]}

Taneja, Nate ^{[1
]}

O'Shea, Jonathan ^{[1
]}

Bisbe, Anna ^{[1
]}

Manoharan, Rajar M. ^{[1
]}

Yucius, Kristina ^{[1
]}

Nguyen, Tuyen ^{[1
]}

Indrakanti, Ramesh ^{[1
]}

Gupta, Swati ^{[1
]}

Gilbert, Jason A. ^{[1
]}

Racie, Tim ^{[1
]}

Chan, Amy ^{[1
]}

Liu, Ju ^{[1
]}

Hutabarat, Renta ^{[1
]}

Nair, Jayaprakash K. ^{[1
]}

Charisse, Klaus ^{[1
]}

Maier, Martin A. ^{[1
]}

Rajeev, Kallanthottathil G. ^{[1
]}

Egli, Martin ^{[2
]}

Manoharan, Muthiah ^{[1
]}

机构：

[1] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA

[2] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年

关键词：

ASIALOGLYCOPROTEIN RECEPTOR; TARGETED DELIVERY; IN-VIVO; RECOGNITION; TRIVALENT; GALACTOSE; LIGAND; OLIGONUCLEOTIDES; HEPATOCYTES; MECHANISM;

D O I：

10.1021/acs.jmedchem.2c01337

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Conjugation of synthetic triantennary N-acetyl-D-galactosamine (GalNAc) to small interfering RNA (siRNA) mediates binding to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes, facilitating liver-specific uptake and siRNA-mediated gene silencing. The natural beta-glycosidic bond of the GalNAc ligand is rapidly cleaved by glycosidases in vivo. Novel GalNAc ligands with S-, and C-glycosides with both alpha- and beta-anomeric linkages, N-glycosides with beta-anomeric linkage, and the O -glycoside with alpha-anomeric linkage were synthesized and conjugated to siRNA either on-column during siRNA synthesis or through a high-throughput, post-synthetic method. Unlike natural GalNAc, modified ligands were resistant to glycosidase activity. The siRNAs conjugated to newly designed ligands had similar affinities for ASGPR and similar silencing activity in mice as the parent GalNAc- siRNA conjugate. These data suggest that other factors, such as protein-nucleic acid interactions and loading of the antisense strand into the RNA-induced silencing complex (RISC), are more critical to the duration of action than the stereochemistry and stability of the anomeric linkage between the GalNAc moiety of the ligand conjugated to the sense strand of the siRNA.

引用

页码：2506 / 2523

页数：18