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Open Access Green as soon as Postprint is submitted to ZB.
Syntheses of morpholine-based nucleotide analogs for hepatic siRNA targeting and stabilization.
J. Med. Chem. 64, 6838–6855 (2021)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Conjugated Antisense Oligonucleotides; Solid-phase Synthesis; Asialoglycoprotein Receptor; In-vivo; High-affinity; Hepatocytes; Delivery; Subunit; Vitro; H1
ISSN (print) / ISBN
0022-2623
e-ISSN
1520-4804
Journal
Journal of Medicinal Chemistry
Quellenangaben
Volume: 64,
Issue: 10,
Pages: 6838–6855
Publisher
American Chemical Society (ACS)
Publishing Place
1155 16th St, Nw, Washington, Dc 20036 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Medicinal Chemistry (IMC)