Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization

authored by: Armin Hofmeister, Kerstin Jahn-Hofmann, Bodo Brunner, Mike W. Helms, Christiane Metz-Weidmann, Arne Krack, Michael Kurz, Ziyu Li, Merle M. Weitzenberg, Elsa Pflimlin, Oliver Plettenburg, Sabine Scheidler
Abstract: 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.
Organisation(s): Institute of Organic Chemistry
External Organisation(s): Helmholtz Zentrum München - German Research Center for Environmental Health
Hospices Civils de Lyon
Sanofi-Aventis Deutschland GmbH
Type: Article
Journal: Journal of medicinal chemistry
Volume: 64
Pages: 6838-6855
No. of pages: 18
ISSN: 0022-2623
Publication date: 27.05.2021
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Molecular Medicine, Drug Discovery
Electronic version(s): https://doi.org/10.1021/acs.jmedchem.1c00144 (Access: Closed)

BibTeX

@article{3bb3182e73cb474fb096f56f1264bd04,
title = "Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization",
abstract = "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.",
author = "Armin Hofmeister and Kerstin Jahn-Hofmann and Bodo Brunner and Helms, {Mike W.} and Christiane Metz-Weidmann and Arne Krack and Michael Kurz and Ziyu Li and Weitzenberg, {Merle M.} and Elsa Pflimlin and Oliver Plettenburg and Sabine Scheidler",
year = "2021",
month = may,
day = "27",
doi = "10.1021/acs.jmedchem.1c00144",
language = "English",
volume = "64",
pages = "6838--6855",
journal = "Journal of medicinal chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "10",
}