Enhancement of RNAi activity by improved siRNA duplexes

Hohjoh, Hirohiko

doi:10.1016/s0014-5793(03)01492-3

Cited by 83 publications

(79 citation statements)

References 21 publications

(27 reference statements)

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“…Another type of RNAi inducer, fork-siRNA, was first introduced by Hohjoh [83]. Fork-siRNAs contain base substitutions in the 3′ end of the sense strand of siRNA, resulting in destabilization of the duplex [83][84][85].…”

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

“…Fork-siRNAs contain base substitutions in the 3′ end of the sense strand of siRNA, resulting in destabilization of the duplex [83][84][85]. The effect of fork-siRNAs is explained by the fact that thermodynamic asymmetry of the duplexes determines the orientation of siRNA in RISC.…”

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

“…To address this issue, the favorable asymmetry can be achieved by the introduction of several base substitutions at the 3′ end of the sense strand. Mismatches at the 3′ end of the sense strand, resulting in the formation of unpaired or destabilized regions, increase the silencing activity of siRNA with low or moderate concentrations [83]. The number of mismatches in fork-siRNA also plays a crucial role in its silencing activity [85].…”

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

“…On the other hand, mismatches in the 3′ part of the sense strand and long unpaired ends increase the sensitivity of fork-siRNA to nucleases. Consequently, the application of non-modified fork-siRNAs in vivo is limited by the fact that they have reduced stability in biological fluids due to the increased degradation by nucleases [83,85]. To solve this problem, the algorithm for designing nuclease-resistant fork-siRNAs that contain 2′-Omethyl modifications in nuclease-sensitive sites was developed, which allows obtaining forksiRNAs whose stability is comparable to that of canonical siRNAs [85].…”

Section: Interfering Rna With Noncanonical Duplex Structurementioning

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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Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

Section: Interfering Rna With Noncanonical Duplex Structurementioning

confidence: 99%

See 2 more Smart Citations

Noncanonical Synthetic RNAi Inducers

Gvozdeva¹,

Chernolovskaya²

2016

RNA Interference

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“…Influence of overhang structures on strand selection and silencing efficiency Several previous studies have suggested that siRNAs with asymmetric overhangs had enhanced efficacy relative to siRNAs with symmetric overhangs [19][20][21][22]. For example, Sano et al showed that siRNAs with a unilateral 2-nt 3¢-overhang on the guide strand are more effective than those with 3¢-overhang at both ends [21].…”

Section: Selective Suppression Of Endogenous Transcript By Sirnas Witmentioning

confidence: 99%

Effect of siRNA with an Asymmetric RNA/dTdT Overhang on RNA Interference Activity

Park

Hong

Yun

et al. 2014

Nucleic Acid Therapeutics

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Small interfering RNAs (siRNAs) guide RNA-induced silencing complexes (RISC) to target mRNAs for sequence-specific silencing. A fundamental aspect of this highly coordinated process is a guide strand-specific loading of the siRNA duplex into the RISC for the accurate target recognition, which is currently dictated by certain duplex parameters such as thermodynamics. Here, we show that minor changes in the overhang structure have profound effects on the extent to which the individual strands of the siRNA duplex participate in RNAi activity. We demonstrate that the two strands of the siRNA are similarly eligible for assembly into RISC for the siRNAs with symmetric overhangs, whereas those with asymmetric RNA/deoxythymidine dinucleotide (dTdT) overhangs exhibit a distinct preference in favor of a strand with an RNA overhang that drives a mature RISC affinity to the desired target. We believe that this additional determinant provides a plausible and simple approach for improving the strand selection, thereby considerably increasing a specificity of target silencing.

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