Development of Bridged Nucleic Acid Analogues for Antigene Technology

Obika, Satoshi

doi:10.1248/cpb.52.1399

Cited by 46 publications

(21 citation statements)

References 70 publications

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“…Considerable efforts have been made to extend the repertoire of potential target DNA sequences and increase the triplex stability while keeping its specificity via chemical modification on TFOs (307,319). To extend the repertoire of target DNA sequences, most efforts focus on synthesis of new nucleobase analogues to avoid the requirement of a polypurine target sequence for TFO binding, i.e., to recognize a pyrimidine which interrupts an oligopurine sequence.…”

Section: Chemical Modifications On Tfosmentioning

confidence: 99%

“…A conformational change to N type in the sugar moiety might also contribute to this enhanced triplex-forming ability (319). It is suggested that the formation of a duplex or triplex is entropically unfavorable due to the restriction in conformational freedom of the furanose ring.…”

Section: Chemical Modifications On Tfosmentioning

confidence: 99%

“…Locked nucleic acid (LNA) is designed to have this "pre-organization" by introducing a bridge between the O2' and C4' atoms, the sugar conformation of which is restricted to the N type (319). As a result, triplex can be formed 300-fold more stable compared with the corresponding one without modification.…”

Section: Chemical Modifications On Tfosmentioning

confidence: 99%

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Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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Section: Chemical Modifications On Tfosmentioning

confidence: 99%

Section: Chemical Modifications On Tfosmentioning

confidence: 99%

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Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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“…This α-tocopherol HDO conjugate showed significantly high specificity for the target and exerted remarkably potent genesilencing efficacy in vivo. Obika and co-workers (11,12) Chemical modification should alter the physicochemical properties of oligonucleotides to affect their distribution in the body. Therefore, a significant increase in affinity and specificity for target genes is considered essential for such synthetic oligonucleotides.…”

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confidence: 99%

Therapeutic oligonucleotides and delivery technologies: Research topics in Japan

Murakami

2016

DD&T

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“…To overcome this problem, extensive research on nucleic acid analogues has so far been carried out. [5][6][7][8] We have focused on the parallel type triplex, and synthesized 2Ј-O,4Ј-C-methylene-bridged nucleic acid (2Ј,4Ј-BNA 5,[9][10][11][12][13] /locked nucleic acid (LNA) 14) ) bearing unnatural nucleobases to recognize pyrimidine-purine interruption in the target dsDNA. [15][16][17][18][19] Recently, it was found that the 2Ј,4Ј-BNA bearing oxazole 15,16) (O B : Fig.…”

mentioning

confidence: 99%

Synthesis and Triplex-Forming Ability of 2',4'-BNAs Bearing Imidazoles as a Nucleobase

Hari

Obika

Inohara

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Triplex-forming oligonucleotide (TFO) is able to hybridize with a double-stranded DNA (dsDNA) target in a sequencespecific manner to form a triplex DNA, and it has attracted great interest because of its applications to gene therapy and diagnosis. [2][3][4] There are two fashions in triplex formation. One is a parallel motif triplex, where a TFO consisting of a homopyrimidine sequence hybridizes with a dsDNA target in parallel with a purine strand of the target duplex via Hoogsteen hydrogen bond. The other is an antiparallel motif triplex, in which the TFO and the purine strand of the duplex are in an antiparallel orientation. In both triplex motifs, the TFOs are able to hybridize only with a homopurine-homopyrimidine tract in the dsDNA target. This is a severe limitation of the practical use of TFOs. To overcome this problem, extensive research on nucleic acid analogues has so far been carried out. [5][6][7][8] We have focused on the parallel type triplex, and synthesized 2Ј-O,4Ј-C-methylene-bridged nucleic acid (2Ј, [9][10][11][12][13] /locked nucleic acid (LNA) 14) ) bearing unnatural nucleobases to recognize pyrimidine-purine interruption in the target dsDNA. [15][16][17][18][19] Recently, it was found that the 2Ј,4Ј-BNA bearing oxazole 15,16) : Fig. 1) and triplex-forming ability of the oligonucleotide derivatives are described. Results and DiscussionSynthesis of 2,4-BNA Monomers and Their TFO Derivatives As shown in Chart 1, 2Ј,4Ј-BNA amidite units bearing imidazole and 2-aminoimidazole were synthesized by using 1 20) as the starting material. Coupling reaction of 1 with 2-nitroimidazoles gave 2b, whereas the reaction of unsubstituted imidazole gave the desired compound 2a along with an imidazolium salt 2a.21) Next, 2a and 2b were reacted with K 2 CO 3 in MeOH to give 3a and 3b. Reduction of 3a and 3b smoothly proceeded to afford 2Ј,4Ј-BNA monomers 4a and 4b, respectively. Protection of an amino group in 4b gave the corresponding N,N-dimethylformamidine derivative 4b. The 5Ј-hydroxy groups of 4a and 4b were then protected with a dimethoxytrityl (DMTr) group to afford 5a and 5b, respectively. The preparation of phosphoramidites 6a and 6b was carried out by phosphitilation of 5a and 5b, respectively. Incorporation of the obtained amidites 6a and 6b into oligonucleotides was successfully achieved by using a standard phosphoramidite method on an automated DNA synthesizer. After purification by reverse-phase HPLC, composition of the oligonucleotides was confirmed by MALDI-TOF-MS. To expand the sequence of double-stranded DNA (dsDNA) targets in a triplex formation, 2,4-BNAs (2-O,4-C-methylene bridged nucleic acids) having imidazoles as a nucleobase were synthesized and incorporated into oligonucleotides. Triplex-forming ability of the modified oligonucleotides was evaluated by using melting temperature (T m ) measurements.Key words methylene bridged nucleic acid (BNA); locked nucleic acid (LNA); triplex; imidazole; oligonucleotide Reagents: a) 1-trimethylsilylimidazole, trimethylsilyl trifluoromethanesulfonate,...

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Development of Bridged Nucleic Acid Analogues for Antigene Technology

Cited by 46 publications

References 70 publications

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Therapeutic oligonucleotides and delivery technologies: Research topics in Japan

Synthesis and Triplex-Forming Ability of 2',4'-BNAs Bearing Imidazoles as a Nucleobase

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