Details
| Original language | English |
|---|---|
| Pages (from-to) | 6838-6855 |
| Number of pages | 18 |
| Journal | Journal of medicinal chemistry |
| Volume | 64 |
| Issue number | 10 |
| Early online date | 5 May 2021 |
| Publication status | Published - 27 May 2021 |
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.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
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In: Journal of medicinal chemistry, Vol. 64, No. 10, 27.05.2021, p. 6838-6855.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization
AU - Hofmeister, Armin
AU - Jahn-Hofmann, Kerstin
AU - Brunner, Bodo
AU - Helms, Mike W.
AU - Metz-Weidmann, Christiane
AU - Krack, Arne
AU - Kurz, Michael
AU - Li, Ziyu
AU - Weitzenberg, Merle M.
AU - Pflimlin, Elsa
AU - Plettenburg, Oliver
AU - Scheidler, Sabine
PY - 2021/5/27
Y1 - 2021/5/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106494876&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00144
DO - 10.1021/acs.jmedchem.1c00144
M3 - Article
C2 - 33950677
AN - SCOPUS:85106494876
VL - 64
SP - 6838
EP - 6855
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
SN - 0022-2623
IS - 10
ER -