Synthesis and Biological Activity of Phosphonocarboxylate DNA

Yamada, Christina M.; Dellinger, Douglas J.; Caruthers, Marvin H.

doi:10.1080/15257770701489896

Cited by 14 publications

(10 citation statements)

References 8 publications

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“…Another alternative is boranophosphate linkages that are more nuclease-resistant and less toxic compared with phosphorothioate [63]. Also, phosphonoacetate linkages are completely resistant to nuclease degradation and are electrochemically neutral (if esterified) [64], which facilitates absorption of modified oligonucleotides by cells even in the absence of delivery reagents [65].…”

Section: Sirna Structure Design and Synthesismentioning

confidence: 99%

Therapeutic face of RNAi:in vivochallenges

Borna

Imani

Iman

et al. 2014

Expert Opinion on Biological Therapy

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Specific, efficient and targeted delivery of siRNAs is the major concern for their in vivo administrations. Also, anatomical barriers, drug stability and availability, immunoreactivity and existence of various delivery routes, different genetic backgrounds are major clinical challenges. However, successful administration of siRNA-based drugs is expected during foreseeable features. But, their systemic applications will depend on strong targeted drug delivery strategies.

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Section: Sirna Structure Design and Synthesismentioning

confidence: 99%

Therapeutic face of RNAi:in vivochallenges

Borna

Imani

Iman

et al. 2014

Expert Opinion on Biological Therapy

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show abstract

“…Both modifications are completely resistant to degradation and PACE is electrochemically neutral if esterified with, e.g., methyl groups (Sheehan et al, 2003), which allows modified oligonucleotides to be taken up by cells in the absence of delivery reagents (Yamada et al, 2007). Also dual modification types combining 2′-OMe and PACT/ThioPACT have recently been tested in siRNA design (see below).…”

Section: Tools For Chemical Modification Of Sirnasmentioning

confidence: 99%

Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering

Bramsen¹,

Kjems²

2012

Front. Gene.

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Recent successes in clinical trials have provided important proof of concept that small interfering RNAs (siRNAs) indeed constitute a new promising class of therapeutics. Although great efforts are still needed to ensure efficient means of delivery in vivo, the siRNA molecule itself has been successfully engineered by chemical modification to meet initial challenges regarding specificity, stability, and immunogenicity. To date, a great wealth of siRNA architectures and types of chemical modification are available for promoting safe siRNA-mediated gene silencing in vivo and, consequently, the choice of design and modification types can be challenging to individual experimenters. Here we review the literature and devise how to improve siRNA performance by structural design and specific chemical modification to ensure potent and specific gene silencing without unwarranted side-effects and hereby complement the ongoing efforts to improve cell targeting and delivery by other carrier molecules.

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“…Phosphonoacetate linkages (Fig. 16.3.4) are recently described backbone modifications with exciting properties (Sheehan et al, 2003;Yamada et al, 2007). These linkages can be esterified, affording nucleic acids with neutral backbones, which can be taken up by cells without transfection reagent (Sheehan et al, 2003;Yamada et al, 2007).…”

Section: Backbone Linkage Modificationsmentioning

confidence: 99%

“…16.3.4) are recently described backbone modifications with exciting properties (Sheehan et al, 2003;Yamada et al, 2007). These linkages can be esterified, affording nucleic acids with neutral backbones, which can be taken up by cells without transfection reagent (Sheehan et al, 2003;Yamada et al, 2007). Cellular esterases are then believed to cleave the ester groups, producing phosphonoacetate backbones, which are negatively charged and thus retained inside cells (Yamada et al, 2007).…”

Section: Backbone Linkage Modificationsmentioning

confidence: 99%

Chemical Modification of siRNA

Deleavey

Watts

Damha

2009

CP Nucleic Acid Chemistry

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The ability to manipulate the RNA interference (RNAi) machinery to specifically silence the expression of target genes could be a powerful therapeutic strategy. Since the discovery that RNAi can be triggered in mammalian cells by short double-stranded RNAs (small interfering RNA, siRNA), there has been a tremendous push by researchers, from academia to big pharma, to move siRNAs into clinical application. The challenges facing siRNA therapeutics are significant. The inherent properties of siRNAs (polyanionic, vulnerable to nuclease cleavage) make clinical application difficult due to poor cellular uptake and rapid clearance. Side effects of siRNAs have also proven to be a further complication. Fortunately, numerous chemical modification strategies have been identified that allow many of these obstacles to be overcome. This unit will present an overview of (1) the chemical modifications available to the nucleic acid chemist for modifying siRNAs, (2) the application of chemical modifications to address specific therapeutic obstacles, and (3) the factors that must be considered when assessing the activity of modified siRNAs.

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Synthesis and Biological Activity of Phosphonocarboxylate DNA

Abstract: Oligodeoxynucleotides containing internucleotide phosphonoacetate esters are taken up irreversibly by cells in culture in the absence of cationic lipids. These oligonucleotides also are active in stimulating RNase H and are stable toward nucleases.

Cited by 14 publications

References 8 publications

Therapeutic face of RNAi:in vivochallenges

Therapeutic face of RNAi:in vivochallenges

Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering

Chemical Modification of siRNA

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