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Hofmeister, A.* ; Jahn-Hofmann, K.* ; Brunner, B.* ; Helms, M.W.* ; Metz-Weidmann, C.* ; Krack, A.* ; Kurz, M.* ; Li, Z.* ; Weitzenberg, M.M. ; Pflimlin, E.* ; Plettenburg, O. ; Scheidler, S.*

Syntheses of morpholine-based nucleotide analogs for hepatic siRNA targeting and stabilization.

J. Med. Chem. 64, 6838–6855 (2021)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Journal of Medicinal Chemistry
Quellenangaben Band: 64, Heft: 10, Seiten: 6838–6855 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Medicinal Chemistry (IMC)