Chemically modified siRNA: tools and applications

Watts, Jonathan K.; Deleavey, Glen F.; Damha, Masad J.

doi:10.1016/j.drudis.2008.05.007

Cited by 398 publications

(358 citation statements)

References 136 publications

Supporting

Mentioning

346

Contrasting

Order By: Relevance

“…Remarkably, the silencing activity of 2'-F-modified siRNAs virtually does not depend on the number of modifications in contrast to 2'-O-Me-modified siRNAs. The silencing activity of siRNAs with 2'-F-modifications in the sense and the antisense strands was compatible with that of unmodified analogs [76]. The replacement of pyrimidine nucleotides in the duplex with 2'-F-analogs was well tolerated by RNAi machinery both in vitro [46,77,73] and in vivo [78].…”

Section: Substituents In Furanosementioning

confidence: 68%

Structure - Functions Relations in Small Interfering RNAs

Petrova¹,

Зенкова²,

Chernolovskaya³

2013

Practical Applications in Biomedical Engineering

View full text Add to dashboard Cite

Section: Substituents In Furanosementioning

confidence: 68%

Structure - Functions Relations in Small Interfering RNAs

Petrova¹,

Зенкова²,

Chernolovskaya³

2013

Practical Applications in Biomedical Engineering

View full text Add to dashboard Cite

“…At the same time, degradation rate of dsiRNAs also correlates with the presence of AU-rich domains that might be related to low thermal stability, easy dissociation, and faster cleavage by both endo-and exonucleases. Chemical modifications can improve nuclease stability and reduce off-target effects [33][34][35][36]. Fluorescein modification of 3′ end of 27-mer RNA duplexes significantly reduces RNAi activity because 3′ ends are important for interaction with Dicer and should be available for the proper recognition [15].…”

Section: Dicer Substrate Interfering Rnasmentioning

confidence: 99%

Noncanonical Synthetic RNAi Inducers

Gvozdeva¹,

Chernolovskaya²

2016

RNA Interference

View full text Add to dashboard Cite

This review focuses on current strategies of development of noncanonical synthetic RNA interference (RNAi) inducers with structural modifications for promoting better gene silencing with low risk of side effects. A particular focus is on longer RNA duplexes 25-30 nucleotides (nt) in length that mimic Dicer substrates to improve interaction of RNAi inducers with RNAi machinery. Various design strategies of efficient Dicer substrate smallinterfering RNA (siRNA) are described. It was found that the length, chemical modifications, and overhang structure influence the gene silencing activity and RNA-induced silencing complex (RISC) assembly. Special attention is paid to the long doublestranded RNA duplexes that induce effective gene silencing in Dicer-dependent or Dicerindependent mode. Some structural variants of shorter siRNAs, including hairpin and dumbbell siRNAs and fork-siRNA (fsiRNA) with several nucleotide substitutions at the 3′ end of the sense strand, are also analyzed. These structural modifications provide efficiently increased gene silencing of targets with unfavorable duplex thermodynamic asymmetry. Recent data remove the length and structure limits for the design of RNAi effectors, and add another example in the list of novel RNAi-inducing molecules differing from the classical siRNA, which is discussed in this chapter.

show abstract

“…Several chemical modifications of siRNAs exist (Behlke 2008; Watts et al. 2008; Shukla et al. 2010; Bramsen and Kjems 2011; Engels 2013) and sugar modifications are the most widely used siRNA modifications compared to backbone and base modifications.…”

Section: Introductionmentioning

confidence: 99%

“…Incorporation of 2′‐ O ‐methyl (2′OMe) has the following positive consequences: (1) full retainment of potency (2) extended stability in serum (3) well tolerated in siRNAs, by lowering the risk towards activation of the innate immune system (Watts et al. 2008; Castanotto and Rossi 2009; Whitehead et al. 2009).…”

Section: Introductionmentioning

confidence: 99%

ADME studies of [5‐³H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics

Lozac'h

Christensen

Faller

et al. 2016

Pharmacology Res & Perspec

View full text Add to dashboard Cite

The chemical modification 2′‐O‐methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)‐properties of tritium‐labeled 2′‐O‐methyluridine, following a single intravenous dose to male CD‐1 mice. The single intravenous administration of [5‐3H]‐2′‐O‐methyluridine was well tolerated in mice. Radioactivity was rapidly and widely distributed throughout the body and remained detectable in all tissues investigated throughout the observation period of 48 h. After an initial rapid decline, blood concentrations of total radiolabeled components declined at a much slower rate. [3H]‐2′‐O‐Methyluridine represented a minor component of the radioactivity in plasma (5.89% of [3H]‐AUC 0‐48 h). Three [3H]‐2′‐O‐methyluridine metabolites namely uridine (M1), cytidine (M2), and uracil (M3) were the major circulating components representing 32.8%, 8.11%, and 23.6% of radioactivity area under the curve, respectively. The highest concentrations of total radiolabeled components and exposures were observed in kidney, spleen, pineal body, and lymph nodes. The mass balance, which is the sum of external recovery of radioactivity in excreta and remaining radioactivity in carcass and cage wash, was complete. Renal excretion accounted for about 52.7% of the dose with direct renal excretion of the parent in combination with metabolism to the endogenous compounds cytidine, uracil, cytosine, and cytidine.

show abstract

Chemically modified siRNA: tools and applications

Cited by 398 publications

References 136 publications

Structure - Functions Relations in Small Interfering RNAs

Structure - Functions Relations in Small Interfering RNAs

Noncanonical Synthetic RNAi Inducers

ADME studies of [5‐³H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics

Contact Info

Product

Resources

About

Chemically modified siRNA: tools and applications

Cited by 398 publications

References 136 publications

Structure - Functions Relations in Small Interfering RNAs

Structure - Functions Relations in Small Interfering RNAs

Noncanonical Synthetic RNAi Inducers

ADME studies of [5‐3H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics

Contact Info

Product

Resources

About

ADME studies of [5‐³H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics