Modulation of DNA and RNA by PNA

Muangkaew, Penthip; Vilaivan, Tirayut

doi:10.1016/j.bmcl.2020.127064

Cited by 30 publications

(28 citation statements)

References 107 publications

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“…While circulating in the bloodstream, nucleic acids remain sensitive to nucleases. Since phosphate is directly involved in nucleic acid cleavage, there were attempts to introduce chemical modifications to this position, such as phosphorothioate (PS) [ 21 ], boranophosphate [ 22 ], N3 phosphoramidate [ 23 ], dimethylethylenediamine [ 24 ], phosphonoacetate [ 25 ], tert -butyl-S-acyl-2-thioethyl [ 26 ], phosphorylguanidine [ 27 ], and mesyl [ 28 ], as well as analogues of nucleic acids with modified structures of the furanose cycle, such as morpholino [ 29 ] and peptide nucleic acid [ 30 ], increasing the nuclease resistance of the preparations. However, today the most frequently used phosphate stabilizing modification of antisense oligonucleotides (asON) is PS, which can cause toxicity due to non-specific interactions of PS-modified oligonucleotides with cell proteins [ 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

et al. 2020

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Biological activity of antisense oligonucleotides (asON), especially those with a neutral backbone, is often attenuated by poor cellular accumulation. In the present proof-of-concept study, we propose a novel delivery system for asONs which implies the delivery of modified antisense oligonucleotides by so-called transport oligonucleotides (tON), which are oligodeoxyribonucleotides complementary to asON conjugated with hydrophobic dodecyl moieties. Two types of tONs, bearing at the 5′-end up to three dodecyl residues attached through non-nucleotide inserts (TD series) or anchored directly to internucleotidic phosphate (TP series), were synthesized. tONs with three dodecyl residues efficiently delivered asON to cells without any signs of cytotoxicity and provided a transfection efficacy comparable to that achieved using Lipofectamine 2000. We found that, in the case of tON with three dodecyl residues, some tON/asON duplexes were excreted from the cells within extracellular vesicles at late stages of transfection. We confirmed the high efficacy of the novel and demonstrated that MDR1 mRNA targeted asON delivered by tON with three dodecyl residues significantly reduced the level of P-glycoprotein and increased the sensitivity of KB-8-5 human carcinoma cells to vinblastine. The obtained results demonstrate the efficacy of lipophilic oligonucleotide carriers and shows they are potentially capable of intracellular delivery of any kind of antisense oligonucleotides.

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Section: Introductionmentioning

confidence: 99%

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

et al. 2020

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“…The ability to detect and modify the genome of living organisms is important for the diagnosis, prevention, and treatment of many diseases [1]. The site-specific targeting and manipulation of genomic DNA or RNA using chemically modified short oligodeoxynucleotides (ONs) is considered to be a viable therapeutic strategy [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Many synthetic analogues of natural ONs, such as peptide nucleic acids (PNA) [20], locked nucleic acids [21] (LNA, also known as bridged nucleic acids (BNA) [22]) and phosphorothioate (PS) ONs [23,24] have been evaluated for antigene/anti-sense applications, however, each of the analogues did not meet all the requirements. For example, both PNA and modified PNAs have excellent chemical stability, are resistant to enzymatic degradation, and have high binding affinity towards complementary DNA and RNA, but have a tendency to aggregate, require high salt conditions, and have low solubility in water [1,25,26]. LNA (BNA) have an enhanced thermal stability in DNA triplexes and duplexes, a high binding affinity to RNA, and are nuclease resistant [22,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

Bayarjargal

Hale

et al. 2021

Beilstein J. Org. Chem.

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Two phosphate modifications were introduced into the DNA backbone using the Staudinger reaction between the 3’,5’-dinucleoside β-cyanoethyl phosphite triester formed during DNA synthesis and sulfonyl azides, 4-(azidosulfonyl)-N,N,N-trimethylbutan-1-aminium iodide (N+ azide) or p-toluenesulfonyl (tosyl or Ts) azide, to provide either a zwitterionic phosphoramidate with N+ modification or a negatively charged phosphoramidate for Ts modification in the DNA sequence. The incorporation of these N+ and Ts modifications led to the formation of thermally stable parallel DNA triplexes, regardless of the number of modifications incorporated into the oligodeoxynucleotides (ONs). For both N+ and Ts-modified ONs, the antiparallel duplexes formed with complementary RNA were more stable than those formed with complementary DNA (except for ONs with modification in the middle of the sequence). Additionally, the incorporation of N+ modifications led to the formation of duplexes with a thermal stability that was less dependent on the ionic strength than native DNA duplexes. The thermodynamic analysis of the melting curves revealed that it is the reduction in unfavourable entropy, despite the decrease in favourable enthalpy, which is responsible for the stabilisation of duplexes with N+ modification. N+ONs also demonstrated greater resistance to nuclease digestion by snake venom phosphodiesterase I than the corresponding Ts-ONs. Cell uptake studies showed that Ts-ONs can enter the nucleus of mouse fibroblast NIH3T3 cells without any transfection reagent, whereas, N+ONs remain concentrated in vesicles within the cytoplasm. These results indicate that both N+ and Ts-modified ONs are promising for various in vivo applications.

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“…The sequence-specific recognition of double-stranded DNA (dsDNA) has been an important research subject owing to its wide range of potential applications [1][2][3][4][5][6][7]. For this purpose, various methods have been developed, including those that make use of DNA-binding proteins [1,[3][4][5][8][9][10][11][12], small molecules such as minor groove binders [13][14][15][16], and artificial DNA [17][18][19][20][21][22][23][24]. In addition, the recognition of dsDNA by peptide nucleic acid (PNA), an artificial nucleic acid mimic, has been reported by Nielsen et al [7,21,[24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Characteristics of NLS-PNA: Influence of NLS Location on Invasion Efficiency

et al. 2020

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Peptide nucleic acid can recognise sequences in double-stranded DNA (dsDNA) through the formation of a double-duplex invasion complex. This double-duplex invasion is a promising method for the recognition of dsDNA in cellula because peptide nucleic acid (PNA) invasion does not require the prior denaturation of dsDNA. To increase its applicability, we developed PNAs modified with a nuclear localisation signal (NLS) peptide. In this study, the characteristics of NLS-modified PNAs were investigated for the future design of novel peptide-modified PNAs.

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Modulation of DNA and RNA by PNA

Cited by 30 publications

References 107 publications

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

Investigation of the Characteristics of NLS-PNA: Influence of NLS Location on Invasion Efficiency

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