Journal ArticleDOI
Novel Dioxane and Morpholino Nucleotide Analogues: Syntheses and RNA-Hybridization Properties.
TLDR
A novel class of nucleotide analogues with a dioxane ring as central scaffold has been developed, and the final thymidine analogues were synthesized with common functionalities for the automated oligonucleotide synthesis.Abstract:
A novel class of nucleotide analogues with a dioxane ring as central scaffold has been developed. Synthetic routes in two diastereomeric series were realized, and the final thymidine analogues were synthesized with common functionalities for the automated oligonucleotide synthesis. The chemical space of the initially derived nucleotides was expanded by changing the central dioxane to analogous morpholine derivatives. This opens up the possibility for further derivatization by attaching different substituents at the morpholine nitrogen. The novel nucleotide building blocks were incorporated into double-stranded RNA sequences, and their hybridization properties investigated by melting-temperature analysis. Both scaffolds, dioxanes and morpholines, had an equal impact on double-strand stability, but Tm values differed depending on the chirality in the six-membered ring.read more
Citations
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Patent
Antisense nucleic acid
TL;DR: The present invention provides an antisense oligomer which enables claim 51 exon skipping in the human dystrophin gene with high efficiency.
Journal ArticleDOI
Small Interfering RNAs Containing Dioxane- and Morpholino-Derived Nucleotide Analogues Show Improved Off-Target Profiles and Chirality-Dependent In Vivo Knock-Down.
Armin Hofmeister,Kerstin Jahn-Hofmann,Bodo Brunner,Mike Helms,Christiane Metz-Weidmann,Arne Krack,Michael Kurz,Christoph Heubel,Sabine Scheidler +8 more
TL;DR: All siRNAs containing these novel nucleotide structures showed improved off-target profiles in vitro compared to their parent sequence with the common 2'-OMe-modified adenosine at the same position, and in vivo potencies were highly dependent on the chirality within the six-membered nucleotide scaffolds and showed high mRNA downregulations for the (2R,6R)-configured diastereomers.
Journal ArticleDOI
Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization
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 +11 more
TL;DR: In this paper, a morpholine-based nucleotide analog was developed as a building block for hepatic siRNA targeting and stabilization, which increased siRNA stability when used as a double 3'-overhang at the sense strand sequence.
References
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Journal ArticleDOI
Antisense oligonucleotides: a new therapeutic principle
Eugen Uhlmann,Anusch Peyman +1 more
Journal ArticleDOI
Morpholino antisense oligomers: design, preparation, and properties.
TL;DR: An overview of the design, preparation, and properties of Morpholino oligos, a novel antisense structural type that solves the sequence specificity problem and provides high and predictable activity in cells.
Journal ArticleDOI
LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition
Alexei A. Koshkin,Sanjay K. Singh,Poul Nielsen,Vivek K. Rajwanshi,Ravindra Kumar,Michael Meldgaard,Carl Erik Olsen,Jesper Wengel +7 more
TL;DR: Studies of mis-matched sequences show that LNA obey the Watson-Crick base pairing rules with generally improved selectivities compared to the corresponding unmodified reference strands.
Journal ArticleDOI
The ups and downs of nucleic acid duplex stability: Structure-stability studies on chemically-modified DNA:RNA duplexes
TL;DR: From results, structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure are determined and C-5-substituted pyrimidines stood out as substantially increasing duplex stability.
Journal ArticleDOI
LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition
TL;DR: A novel class of nucleic acid analogues, termed LNA (locked nucleic acids), is introduced following the Watson–Crick base pairing rules, which forms duplexes with complementary DNA and RNA with remarkably increased thermal stabilities and generally improved selectivities.