2-Modified Oligonucleotides for Antisense Therapeutics

Prakash, Thazha P.; Bhat, Balkrishen

doi:10.2174/156802607780487713

Cited by 98 publications

(65 citation statements)

References 49 publications

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“…Another way to address this problem is to assemble carbohydrate-modified ONs, exemplified by hexitol nucleic acids [10][11][12][13][14], 2'-O-(2-methoxy)ethyl ONs [15,16] and bicyclic ONs [17], with the LNA monomers of the Wengel group [18] showing the strongest affinity for RNA, and having many alternative structures [19]. The strong hybridization characteristics between these structures and complementary RNA are generally attributed to the formation of a preorganized conformation, fitting the A-form of dsRNA, with strong stacking interactions between the bases, adequate interaction of the latter in a Watson-Crick type geometry with their complement, and efficient hydration of the double-stranded helix [20].…”

Section: Introductionmentioning

confidence: 99%

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

2012

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Abstract:A series of 3'-O-methylated D-altrohexitol nucleoside analogs (MANA) was synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. These monomers were incorporated into While the specificity of these new synthons is slightly lower compared to mismatches within RNA double strands, it is similar to the discrimination potential of other hexitol modifications (HNA and ANA) which already proved their biologic interest, highlighting the potential of MANA constructs in antisense and in siRNA applications.3

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Section: Introductionmentioning

confidence: 99%

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

2012

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“…The 2′-position of the sugar moiety can also serve as a modification site. 2′-methoxy (2′-O-methyl) substituted oligonucleotides were found to form very stable double strands and exhibit significant nuclease resistance, which further facilitates in vivo administration [14][15][16][17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides

Nyakas

Stucki

Schürch

2011

J. Am. Soc. Mass Spectrom.

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Therapeutic approaches for treatment of various diseases aim at the interruption of transcription or translation. Modified oligonucleotides, such as 2′-O-methyl-and methylphosphonatederivatives, exhibit high resistance against cellular nucleases, thus rendering application for, e.g., antigene or antisense purposes possible. Other approaches are based on administration of cross-linking agents, such as cis-diamminedichloroplatinum(II) (cisplatin, DDP), which is still the most widely used anticancer drug worldwide. Due to the formation of 1,2-intrastrand cross links at adjacent guanines, replication of the double-strand is disturbed, thus resulting in significant cytotoxicity. Evidence for the gas-phase dissociation mechanism of platinated RNA is given, based on nano-electrospray ionization high-resolution multistage tandem mass spectrometry (MS n ). Confirmation was found by investigating the fragmentation pattern of platinated and unplatinated 2′-methoxy oligoribonucleotide hexamers and their corresponding methylphosphonate derivatives. Platinated 2′-methoxy oligoribonucleotides exhibit a similar gas-phase dissociation behavior as the corresponding DNA and RNA sequences, with the 3′-C-O bond adjacent to the vicinal guanines being cleaved preferentially, leading to w x -ion formation. By examination of the corresponding platinated methylphosphonate derivatives of the 2′-methoxy oligoribonucleotides, the key role of the negatively charged phosphate oxygen atoms in direct proximity to the guanines was proven. The significant alteration of fragmentation due to platination is demonstrated by comparison of the fragment ion patterns of unplatinated and platinated 2′-O-methyl-and 2′-O-methyl methylphosphonate oligoribonucleotides, and the results obtained by H/D exchange experiments.

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“…These hybrid DNA:RNA and 21 nucleotide-long AS-ONs hybridize to their target mRNA and induce its degradation by RNaseH. This type of modified AS-ONs has been shown to efficiently suppress/ knock down expression of genes and has already been used to develop AS-ON-based therapies in clinical trials for different diseases, including cancer (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Dzwonek

Preobrazhenska

Cazzola

et al. 2009

Molecular Cancer Research

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Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed, including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases, and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342-53)

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2-Modified Oligonucleotides for Antisense Therapeutics

Cited by 98 publications

References 49 publications

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

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