42‐ and 63‐bp anti‐MDR1‐siRNAs bearing 2′‐OMe modifications in nuclease‐sensitive sites induce specific and potent gene silencing

Gvozdeva, Olga V.; Dovydenko, Ilya; Venyaminova, Alya G.; Zenkova, Marina A.; Vlassov, Valentin V.; Chernolovskaya, E. L.

doi:10.1016/j.febslet.2014.02.015

Cited by 11 publications

(16 citation statements)

References 24 publications

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“…Since chemical modifications can block the immune response, we supposed that theoretically nothing prevents the use of partly modified dsRNAs of any length. Previously, we used selectively modified RNA duplexes 21, 42, and 63 bp in length targeting MDR1 mRNA and examined their ability to silence expression of the target gene and the specificity of their action [13]. We showed that 42-and 63-bp siRNAs induced more effective RNAi at lower concentrations than classical 21-bp siRNA without nonspecific immune effects acting in a Dicer-independent mode [13].…”

Section: Edited By Tamas Dalmaymentioning

confidence: 99%

Nuclease‐resistant 63‐bp trimeric siRNAs simultaneously silence three different genes in tumor cells

et al. 2017

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We designed a multimeric nuclease-resistant 63-bp trimeric small-interfering RNA (tsiRNA) comprising in one duplex the sequence of siRNAs targeting mRNAs of MDR1, LMP2, and LMP7 genes. We show that such tsiRNA is able to suppress the expression of all the target genes independently and with high efficiency, acting via a Dicer-dependent mechanism. tsiRNA is diced into 42-and 21-bp duplexes inside the cell. tsiRNA-induced gene silencing is characterized by kinetics similar to that of canonical siRNA, while the silencing efficiency is significantly higher than that of canonical siRNA with the same sequence.

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Section: Edited By Tamas Dalmaymentioning

confidence: 99%

Nuclease‐resistant 63‐bp trimeric siRNAs simultaneously silence three different genes in tumor cells

et al. 2017

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“…The early attempts to use the similar structures for efficient knockdown of target genes in mammalian cells failed due to activation of interferon response [4,94]. Later, various design strategies have been developed to prevent the induction of interferon response and construct new potent RNAi inducers [21,95,96]. Depending on the architecture of duplexes, all long dsRNAs may be divided into linear and branched structures.…”

Section: Long-interfering Rnasmentioning

confidence: 99%

“…Partial 2′-O-methyl modification effectively prevents the activation of interferon response by Dicer-substrate RNAs [17]; therefore, it was proposed to use similar approach for longer linear duplexes [21]. Longer siRNAs containing the sequence of canonical siRNAs repeated two and three times are called dimer (42 nt in length) and trimer (63 nt in length) small-interfering RNA.…”

Section: Long-interfering Rnasmentioning

confidence: 99%

“…Selectively modified dimer and trimer siRNAs, unlike the unmodified ones, did not induce interferon response in cultured cells. The trimers (called tsiRNA) were significantly more active at lower dose-equivalent (per moles of 21 bp) concentrations than their canonical analogues but the silencing effect develops more slowly [21] and acts in a Dicer-independent mode, presumably via direct RISC loading. Although the Dicer cleavage sites were free from modifications, modifications in flanking regions of tsiRNAs could inhibit the Dicer cleavage.…”

Section: Long-interfering Rnasmentioning

confidence: 99%

“…Special attention has been paid to the long double-stranded RNA duplexes, which induced effective gene silencing and did not require Dicer-mediated processing of the substrate into smaller units: trimer RNA (tsiRNA) with 63 nt in length and tripartite-interfering RNA (tiRNA) with 38 nt in length [21,22]. Applications of some structure variations of shorter siRNAs and the potential of different synthetic RNAi inducers in different applications have also been reviewed and summarized.…”

Section: Introductionmentioning

confidence: 99%

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Noncanonical Synthetic RNAi Inducers

Gvozdeva¹,

Chernolovskaya²

2016

RNA Interference

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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.

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Modifications in Therapeutic Oligonucleotides Improving the Delivery

Dovydenko¹,

Venyaminova²,

Pyshnyi³

et al. 2016

Modified Nucleic Acids in Biology and Medicine

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Introduction: Nucleic Acids' Delivery Systems 2 Carrier-Free Targeting Systems 2.1 Nucleic Acids' Conjugation with Targeting Ligands 2.2 Conjugates with Carbohydrates 2.3 Conjugates with Peptides and Aptamers 2.4 Lipid-Containing Conjugates 3 Modifications Improving the Stability of Nucleic Acids 4 Modifications of the Therapeutic RNA Imported into Human Mitochondria 5 Conclusion and Future Prospects . ReferencesAbstract Oligonucleotides are increasingly used in clinical applications. RNA-based therapeutics include inhibitors of mRNA translation, agents of RNA interference, ribozymes, and aptamers targeting various molecular targets. Challenges with the delivery, specificity, and stability of these therapeutics have spawned the development of chemically modified oligonucleotides. In this chapter, we will describe modifications improving delivery and stability of RNA molecules in human cells. Because the most of the cell transfection methods using oligonucleotide complexes with cationic lipids revealed to be toxic, specific modifications and various conjugates have been recently developed to promote the carrier-free

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42‐ and 63‐bp anti‐MDR1‐siRNAs bearing 2′‐OMe modifications in nuclease‐sensitive sites induce specific and potent gene silencing

Cited by 11 publications

References 24 publications

Nuclease‐resistant 63‐bp trimeric siRNAs simultaneously silence three different genes in tumor cells

Nuclease‐resistant 63‐bp trimeric siRNAs simultaneously silence three different genes in tumor cells

Noncanonical Synthetic RNAi Inducers

Modifications in Therapeutic Oligonucleotides Improving the Delivery

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