Activity of siRNAs with 2-Thio-2′-<i>O</i>-Methyluridine Modification in Mammalian Cells

Prakash, Thazha P.; Naik, Nishant; Sioufi, Namir; Swayze, Eric E.

doi:10.1080/15257770903316145

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…In most cases, activating PKR is an unwanted side effect. High translation and low immunogenicity make mRNA containing Ψ or m5C applicable to express therapeutic proteins, whereas s2U-modified RNA is best suited for applications where avoiding nonspecific immunogenicity is desirable but where translation is unnecessary (33), such as delivering antisense RNA (55) or stimulating RNA interference.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation

Anderson

Muramatsu

Nallagatla

et al. 2010

Nucleic Acids Research

511

379

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Previous studies have shown that the translation level of in vitro transcribed messenger RNA (mRNA) is enhanced when its uridines are replaced with pseudouridines; however, the reason for this enhancement has not been identified. Here, we demonstrate that in vitro transcripts containing uridine activate RNA-dependent protein kinase (PKR), which then phosphorylates translation initiation factor 2-alpha (eIF-2α), and inhibits translation. In contrast, in vitro transcribed mRNAs containing pseudouridine activate PKR to a lesser degree, and translation of pseudouridine-containing mRNAs is not repressed. RNA pull-down assays demonstrate that mRNA containing uridine is bound by PKR more efficiently than mRNA with pseudouridine. Finally, the role of PKR is validated by showing that pseudouridine- and uridine-containing RNAs were translated equally in PKR knockout cells. These results indicate that the enhanced translation of mRNAs containing pseudouridine, compared to those containing uridine, is mediated by decreased activation of PKR.

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Section: Discussionmentioning

confidence: 99%

Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation

Anderson

Muramatsu

Nallagatla

et al. 2010

Nucleic Acids Research

511

379

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“…Although nucleoside suppressors of both TLR3 and TLR7/8 have been described (Karikó, Buckstein, Ni, & Weissman, 2005) (Table 1), their impact on siRNA-mediated TLR3 activation has not been assessed. Presently, reports on the impact of 2-thiouridine on slicer function are contradictory (Prakash, Naik, Sioufi, Bhat, & Swayze, 2009;Sipa et al, 2007). Overall, judicious use of one or two 2' modified nucleosides as formulation adjuncts (e.g.…”

Section: Sirna and Mirna Mediated Immune Responsesmentioning

confidence: 99%

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Moschos

Usher

Lindsay

2017

Pharmacology & Therapeutics

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The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

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“…The solid supports of this family have successfully been applied in the synthesis of natural oligoribonucleotides and their 2 -F-analogs (Prakash et al, 2005(Prakash et al, , 2009Tedebark et al, 2011, Lima et al, 2012, LNA oligonucleotides (Ravikumar et al, 2008), oligonucleotides containing 2 ,4 -(Nmethoxy)aminomethylene-, 2 ,4 -aminooxymethylene-, and 2 -O,4 -C-aminomethylenebridged nucleoside analogs (Prakash et al, 2010), and oxepane and 2 -enopyranose nucleoside analogs (Sabatino and Damha, 2007).…”

Section: 112mentioning

confidence: 99%

Solid‐Phase Supports for Oligonucleotide Synthesis

Guzaev¹

2013

CP Nucleic Acid Chemistry

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This unit attempts to provide a reasonably complete inventory of over 280 solid supports available to oligonucleotide chemists for preparation of natural and 3'-modified oligonucleotides. Emphasis is placed on non-nucleosidic solid supports. The relationship between the structural features of linkers and their behavior in oligonucleotide synthesis and deprotection is discussed wherever the relevant observations are available.

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Activity of siRNAs with 2-Thio-2′-O-Methyluridine Modification in Mammalian Cells

Cited by 6 publications

References 31 publications

Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation

Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Solid‐Phase Supports for Oligonucleotide Synthesis

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