Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-<i>O</i>-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Kotikam, Venubabu; Arzumanov, Andrey A.; Gait, Michael J.; Kumar, Vaijayanti A.

doi:10.4161/adna.27279

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…Another potential benefit of siRNA conjugation to serinol-linked GalNAc units is the serinol itself. It has previously been described that serinol capping of terminal positions in 2-OMe RNA splice switching single-stranded oligonucleotides results in increased serum stability over 24 h, 32 as well as increased anti-miR-activity for 3 0 /5 0 serinyl capped 2 0 -OMe-RNA. 33 Similar observations were made for siRNA with phosphodiester-linked serinol nucleic acids in the 3 0 end of the antisense, as well as in the 5 0 and 3 0 ends of the sense strand, which can increase both in vitro stability against exonuclease attack and in vitro activity through preventing sense strand loading.…”

Section: Discussionmentioning

confidence: 99%

Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Weingärtner

Bethge

Weiss

et al. 2020

Molecular Therapy - Nucleic Acids

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N-acetyl-galactosamine (GalNAc) conjugation enhances liver specificity for therapeutic oligonucleotides. Here we report on a novel design with improved activity and stability compared with a triantennary design. We applied a versatile monovalent serinol-GalNAc conjugation strategy. First, 1-4 serial serinol-linked GalNAc units were conjugated to terminal positions of small interfering RNA (siRNA) molecules. In primary hepatocytes, 5 0 antisense GalNAc conjugates were inactive, whereas 3 0 antisense and 3 0 or 5 0 sense conjugates displayed low activity for single GalNAc units, while 2-4 serial GalNAc conjugates were all equally potent. In mice, 5 0 sense conjugates with 2-4 serial GalNAc units were all as potent as a triantennary GalNAc control (1 mg/kg). Second, increased spacing between two serial 5 0 sense-conjugated GalNAc units did not affect in vitro activity. Finally, two single GalNAc units were positioned at opposite ends of the sense strand. A single dose (0.3 mg/kg) of this novel conjugate in mice showed a 3-fold reduction of serum target protein level at day 7 and 4-fold lower serum level at day 27, relative to an equimolar dose of a triantennary GalNAc conjugate of the same siRNA. Improved tritosome stability (by liquid chromatography-mass spectrometry [LC-MS] analysis) can at least partially explain the increased activity and duration of action for the novel GalNAc conjugate.

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Section: Discussionmentioning

confidence: 99%

Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Weingärtner

Bethge

Weiss

et al. 2020

Molecular Therapy - Nucleic Acids

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“…101 Scientists at Silence Pharmaceuticals developed various serinol phosphorothioate-linked GalNAc siRNA conjugates. 102 They had previously shown that capping 5 0 /3 0 termini in 2 0 -OMe-RNA with serinol resulted in increased activity and serum stability over 24 h, 103,104 and so investigated the use of GalNAcylated versions of this building block (25) for targeted delivery of siRNA (Fig. 9).…”

Section: Further Development Of Multivalent Galnac Oligonucleotidesmentioning

confidence: 99%

Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions

Kumar

Turnbull

2023

Chem. Soc. Rev.

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Inhibition of miR-21 by 3′/5′-Serinyl-Capped 2′-O-Methyl RNA Interspersed with 2′-O-(2-Amino-3-Methoxypropyl) Uridine Units

Nahar

Kotikam

Kumar

et al. 2016

Nucleic Acid Therapeutics

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miRNAs are highly conserved class of small ncRNAs whose involvement in human pathophysiologies is extensively investigated. MiR-21 is a well established oncogenic miRNA whose deregulation plays a significant role in onset and progression of cancer. The need of novel approaches to downregulate miR-21 is rapidly expanding. Potent inhibition of miR-21 is achieved by chemically modified 2'-O-methyl RNA oligonucleotide. The serinol capping at 3' and 5'ends and the interspersed 2'-O-(R-2-amino-3-methoxypropyl) uridine units enhance the nuclease resistance and efficacy of 2'-O-methyl RNA for the inhibition of miR-21. This represents a simple and novel modification for developing oligonucleotide-based therapeutics.

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Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-O-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Cited by 3 publications

References 31 publications

Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions

Inhibition of miR-21 by 3′/5′-Serinyl-Capped 2′-O-Methyl RNA Interspersed with 2′-O-(2-Amino-3-Methoxypropyl) Uridine Units

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