Using Chemical Modification to Enhance siRNA Performance

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

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“…486 siRNAs can be delivered indirectly by using viral vectors ( e.g. , lentiviral vectors) that encode one or a few shRNAs (see Figure 27).…”

Section: In Vivo Treatment (“Particle-based Delivery”)mentioning

confidence: 99%

Diverse Applications of Nanomedicine

Pelaz¹,

et al. 2017

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“…The recent FDA approval of Kynamro (3) has shed a new light in the development of nucleic acid based therapeutic drugs. Current efforts in the design of AON and siRNAs involves modification of the sugar phosphate backbone to improve delivery, efficacy, specificity, and stability (2), (4).…”

Section: Introductionmentioning

confidence: 99%

Locked 2′-Deoxy-2′,4′-Difluororibo Modified Nucleic Acids: Thermal Stability, Structural Studies, and siRNA Activity

et al. 2015

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2′-Deoxy-2′,4′-difluorouridine (2′,4′-diF-rU) was readily incorporated into DNA and RNA oligonucleotides via standard solid phase synthesis protocols. NMR and thermal denaturation (T m) data of duplexes was consistent with the 2′,4′-diF-rU nucleotides adopting a rigid North (RNA-like) sugar conformation, as previously observed for the nucleoside monomer. The impact of this modification on T m is neutral when incorporated within RNA:RNA duplexes, mildly destabilizing when located in the RNA strand of a DNA:RNA duplex, and highly destabilizing when inserted in the DNA strand of DNA:RNA and DNA:DNA duplexes. Molecular dynamics calculations suggest that the destabilization effect in DNA:DNA and DNA:RNA duplexes is the result of structural distortions created by A/B junctions within the helical structures. Quantum mechanics calculations suggest that the “neutral” effect imparted to A-form duplexes is caused by alterations in charge distribution that compensate the stabilizing effect expected for a pure North-puckered furanose sugar. 2′,4′-diF-RNA modified siRNAs were able to trigger RNA interference with excellent efficiency. Of note, incorporation of a few 2′,4′-diF-rU residues in the middle of the guide (antisense) strand afforded siRNAs that were more potent than the corresponding siRNAs containing LNA and 2′-F-ANA modifications, and as active as the 2′-F-RNA modified siRNAs.

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“…The introduction of functional diversity at the nucleic acid backbone has proven to be of importance for the development of new ligands (aptamers, siRNA; Bramsen, Grünweller, Hartmann, & Kjems, 2014;Ruckman et al, 1998), catalysts (XNAZymes; Taylor & Holliger, 2015), and nanostructures with potential applications as new materials (XNA origami; Taylor et al, 2016). Indeed, XNAs can have physicochemical properties that make them highly relevant to biomedical and biotechnological applications: Higher resistance to nucleases, increased duplex stability (to DNA, RNA, or to the XNA itself), improved pharmacokinetic properties, and reduced immunogenic potential (Bramsen et al, 2014;Pinheiro & Holliger, 2014).…”

Section: Background Informationmentioning

confidence: 99%

Xenobiotic Nucleic Acid (XNA) Synthesis by Phi29 DNA Polymerase

Torres

Pinheiro

2018

CP Chemical Biology

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Phi29 DNA polymerase (DNAP) is the replicative enzyme of the Bacillus subtilis bacteriophage Phi29. Its extraordinary processivity and its ability to perform isothermal amplification of DNA are central to many molecular biology applications, including high-sensitivity detection and large-scale production of DNA. We present here Phi29 DNAP as an efficient catalyst for the production of various artificial nucleic acids (XNAs) carrying backbone modifications such as 1,5-anhydrohexitol nucleic acid (HNA), 2'-deoxy-2'-fluoro-arabinonucleic acid (FANA), and 2'-fluoro-2'-deoxyribonucleic acid (2'-fluoro-DNA). A full protocol for the synthesis of HNA polymers by an exonuclease-deficient variant (D12A) of Phi29 DNAP plus a detailed guide for the design and test of novel XNA synthetase reactions performed by Phi29 DNAP are provided. © 2018 by John Wiley & Sons, Inc.

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Using Chemical Modification to Enhance siRNA Performance

Cited by 8 publications

References 198 publications

Diverse Applications of Nanomedicine

Diverse Applications of Nanomedicine

Locked 2′-Deoxy-2′,4′-Difluororibo Modified Nucleic Acids: Thermal Stability, Structural Studies, and siRNA Activity

Xenobiotic Nucleic Acid (XNA) Synthesis by Phi29 DNA Polymerase

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