Enhanced Light-Activated RNA Interference Using Phosphorothioate-Based dsRNA Precursors of siRNA

Kala, Ashish; Friedman, Simon H.

doi:10.1007/s11095-011-0529-z

Cited by 24 publications

(16 citation statements)

References 18 publications

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“…One of the possible reasons for the partial inhibition of gene silencing by the photocaged siRNA (35% knockdown without photoirradiation) could be explained by the partial loss of terminal photoreactive units due to nuclease degradation. Friedman et al have first improved their system using phosphorothioate (PS) internucleoside linkages to enhance nuclease resistance near the terminal caged phosphates preventing unwanted loss of the photoreactive moieties before photoirradiation [ 75 ]. This was the case when two PS linkages were introduced into each strand of caged siRNAs.…”

Section: Reviewmentioning

confidence: 99%

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Debart¹,

Dupouy²,

Vasseur³

2018

Beilstein J. Org. Chem.

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Oligonucleotides (ONs) have been envisaged for therapeutic applications for more than thirty years. However, their broad use requires overcoming several hurdles such as instability in biological fluids, low cell penetration, limited tissue distribution, and off-target effects. With this aim, many chemical modifications have been introduced into ONs definitively as a means of modifying and better improving their properties as gene silencing agents and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug under different stimuli. The interest in stimuli-responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be sought.This review examines ON modifications in response to various stimuli. These stimuli may be internal or external to the cell, chemical (glutathione), biochemical (enzymes), or physical (heat, light). For each stimulus, the discussion has been separated into sections corresponding to the site of the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in this review, no application for controlling gene expression has been shown, but a certain potential in this field could be demonstrated. Additionally, other applications in different domains have been mentioned to extend the interest in such molecules.

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Section: Reviewmentioning

confidence: 99%

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Debart¹,

Dupouy²,

Vasseur³

2018

Beilstein J. Org. Chem.

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“…Der Effekt der Nukleobasenmodifizierung auf die Duplexstabilität wurde systematisch untersucht. [152] Eine ähnliche Studie führten Monroe et al mit 2'-Fluor-modifizierten siRNAs durch -sowohl in der Zellkultur als auch in Zebrafischembryonen. Während die Modifikationen des Typs (a), (b) und (d) (Abbildung 6) normalerweise mit geeigneten Bausteinen in der Festphasensynthese hergestellt werden, wird Typ (c) durch eine (unspezifische, statistische) Alkylierung der Oligonukleotide mit einem Diazoderivat der Schutzgruppe erhalten.…”

Section: Andere Anwendungenunclassified

Lichtgesteuerte Werkzeuge

Brieke

Rohrbach

Gottschalk³

et al. 2012

Angewandte Chemie

249

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Die zeitliche und räumliche Kontrolle über chemische und biologische Prozesse spielt eine Schlüsselrolle im Leben, wo das Ganze oft viel mehr ist als die Summe seiner Einzelteile. Trivialerweise bilden die Moleküle einer Zelle noch lange kein lebendiges System aus, wenn sie lediglich willkürlich angeordnet werden. Wenn wir diese Zusammenhänge und die Probleme, die durch Fehlfunktionen entstehen, verstehen wollen, benötigen wir Werkzeuge, mit denen wir komplexe Experimente für diese Fragestellungen entwickeln können. Externe Triggersignale, mit denen wir präzise bestimmen können, wo, wann und in welchem Ausmaß ein Prozess gestartet oder gestoppt wird, sind dafür äußerst wertvoll. Licht ist solch ein ideales Triggersignal: Es ist hoch selektiv und bei richtiger Anwendung unschädlich. Es kann mit gut etablierten Techniken erzeugt und manipuliert werden, und viele Ansätze existieren, um Licht in lebenden Systemen anzuwenden – von Zellen bis zu höheren Organismen. Dieser Aufsatz wird sich mit den aktuellen Entwicklungen der letzten sechs Jahre befassen und die zugrundeliegenden Technologien sowie ihre Anwendungen diskutieren.

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“…Friedman et al reported DNMPE-caged double-stranded siRNAs to photomodulate the silencing of GFP expression without interrupting RFP expression in the cells. 31 – 33 Using a similar approach, 2′-F substituted siRNAs were caged and their RNAi activities on transient GFP repression were photomodulated in zebrafish embryos with spatial resolution. 41 The number of caging groups per siRNA increased with higher DMNPE diazo concentration.…”

Section: Introductionmentioning

confidence: 99%

Caged circular siRNAs for photomodulation of gene expression in cells and mice

et al. 2018

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Enhanced Light-Activated RNA Interference Using Phosphorothioate-Based dsRNA Precursors of siRNA

Abstract: Incorporating phosphorothioate groups into dsRNA both stabilizes them towards degradation by serum enzymes, as well as improves them as the basis for light-activated RNA interference.

Cited by 24 publications

References 18 publications

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Lichtgesteuerte Werkzeuge

Caged circular siRNAs for photomodulation of gene expression in cells and mice

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