Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization
| Autor: | Christiane Metz-Weidmann, Elsa Pflimlin, Kerstin Jahn-Hofmann, Ziyu Li, Bodo Brunner, Sabine Scheidler, Armin Hofmeister, Merle M Weitzenberg, Arne Krack, Mike W Helms, Oliver Plettenburg, Michael Kurz |
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| Rok vydání: | 2021 |
| Předmět: |
Small interfering RNA
Acetylgalactosamine Morpholino Stereochemistry Morpholines RNA Stability Ligands 01 natural sciences Mice 03 medical and health sciences chemistry.chemical_compound In vivo Morpholine Drug Discovery Animals Prealbumin Nucleotide RNA Small Interfering Cells Cultured 030304 developmental biology chemistry.chemical_classification 0303 health sciences Nucleotides Chemistry Ligand (biochemistry) 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Sense strand Hepatocytes Molecular Medicine Female RNA Interference lipids (amino acids peptides and proteins) Linker |
| Zdroj: | Journal of Medicinal Chemistry. 64:6838-6855 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A morpholine-based nucleotide analog was developed as a building block for hepatic siRNA targeting and stabilization. Attachment of an asialoglycoprotein-binding GalNAc ligand at the morpholine nitrogen was realized with different linkers. The obtained morpholino GalNAc scaffolds were coupled to the sense strand of a transthyretin-targeting siRNA and tested for their knockdown potency in vitro and in vivo. A clear structure-activity relationship was developed with regard to the linker type and length as well as the attachment site of the morpholino GalNAc moieties at the siRNA sense strand. Further, simple alkylation of the morpholine nitrogen led to a nucleotide analog, which increased siRNA stability, when used as a double 3'-overhang at the sense strand sequence. Combination of the best morpholino GalNAc building blocks as targeting nucleotides with an optimized stabilizing alkyl-substituted morpholine as 3'-overhangs resulted in siRNAs without any phosphorothioate stabilization in the sense strand and clearly improved the duration of action in vivo. |
| Databáze: | OpenAIRE |
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