Towards the Sequence‐Selective Recognition of Double‐Stranded DNA Containing Pyrimidine‐Purine Interruptions by Triplex‐Forming Oligonucleotides

Hari, Yoshiyuki; Obika, Satoshi; Imanishi, Takeshi

doi:10.1002/ejoc.201101821

Cited by 66 publications

(44 citation statements)

References 143 publications

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“…3 Due to the limited number of suitable Hoogsteen base pairs (usually only the homopurine stretches of the duplex can be targeted) and their pH dependency (C:G*C H+ ), 4,5 a remarkable effort to increase the thermodynamic stability of triple helical structure, especially under physiological conditions, has been done. Sugar/phosphate backbone-and base-modified TFOs [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but also with the aid of triplex stabilizing ligands, which by covalent incorporation into TFOs may provide a sequenceindependent extra binding motif, have been studied. [23][24][25][26][27][28][29][30] Regarding the ligand discovery, the ability of aminoglycosides in stabilizing the DNA and RNA triplexes and their hybrid triplexes has thoroughly been studied by Arya et al [31][32][33][34] Among this carbohydrate family, neomycin has proven to be the most effective triplex stabilizing groove binder.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of C-5, C-2′ and C-4′-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes

Tähtinen¹,

Granqvist²,

Virta³

2015

Bioorganic & Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Synthesis of C-5, C-2′ and C-4′-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes

Tähtinen¹,

Granqvist²,

Virta³

2015

Bioorganic & Medicinal Chemistry

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“…Examples of major advances toward this end include triplex forming oligonucleotides (TFOs), 1 peptide nucleic acids (PNAs), 2,3 and minor groove binding polyamides, 4–6 which were followed by optimized TFOs and PNAs that can be applied across a broader range of targets. 7–16 More recently, engineered proteins such as CRISPR/Cas have gained widespread popularity, 17 despite concerns regarding inadequate binding specificity and cellular delivery. 18 Many DNA targeting applications will benefit from simpler hybridization-based probes that enable rapid, potent, and specific recognition of mixed-sequence dsDNA under physiologic conditions.…”

Section: Introductionmentioning

confidence: 99%

Recognition of mixed-sequence DNA using double-stranded probes with interstrand zipper arrangements of O2′-triphenylene- and coronene-functionalized RNA monomers

et al. 2017

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Development of hybridization-based probes that enable recognition of specific mixed-sequence double-stranded DNA (dsDNA) regions is of considerable interest due to their potential applications in molecular biology, biotechnology, and medicine. We have recently demonstrated that double-stranded probes with +1 interstrand zipper arrangements of intercalator-functionalized nucleotides such as 2′-O-(pyren-1-yl)methyl RNA monomers are inherently activated for recognition of mixed-sequence dsDNA targets, including chromosomal DNA. In the present work, we follow up on our previous structure-activity relationship studies and explore if the dsDNA-recognition efficiency of these so-called Invader probes can be improved by using larger intercalators than pyrene. Oligodeoxyribonucleotides modified with 2′-O-(triphenylen-2-yl)methyl-uridine monomer X and 2′-O-(coronen-1-yl)methyl-uridine monomer Z form extraordinarily stabilized duplexes with complementary DNA (ΔTm’s per modification of up to 13 °C and 20 °C, respectively). Invader probes based on X- and Z-monomers are shown to recognize model dsDNA targets with exceptional binding specificity, but are less efficient than reference probes modified with 2′-O-(pyren-1-yl)methyl-uridine monomer Y. The insight from this study will inform further optimization of Invader probes.

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“…Approaches with more relaxed sequence requirements have been developed but they still require the presence of purine stretches, a circumstance that may not be met at a target of interest. 7 Other strategies allow recognition of mixed-sequence target regions that are unusually accessible to exogenous agents, such as AT-rich cruciforms or transcription bubbles. 8 …”

Section: Introductionmentioning

confidence: 99%

Recognition of double-stranded DNA using energetically activated duplexes with interstrand zippers of 1-, 2- or 4-pyrenyl-functionalized O2′-alkylated RNA monomers

et al. 2014

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Despite advances with triplex-forming oligonucleotides, peptide nucleic acids, polyamides and - more recently - engineered proteins, there remains an urgent need for synthetic ligands that enable specific recognition of double-stranded (ds) DNA to accelerate studies aiming at detecting, regulating and modifying genes. Invaders, i.e., energetically activated DNA duplexes with interstrand zipper arrangements of intercalator-functionalized nucleotides, are emerging as an attractive approach toward this goal. Here, we characterize and compare Invaders based on 1-, 2- and 4-pyrenyl-functionalized O2′-alkylated uridine monomers X–Z by means of thermal denaturation experiments, optical spectroscopy, force-field simulations and recognition experiments using DNA hairpins as model targets. We demonstrate that Invaders with +1 interstrand zippers of X or Y monomers efficiently recognize mixed-sequence DNA hairpins with single nucleotide fidelity. Intercalator-mediated unwinding and activation of the double-stranded probe, coupled with extraordinary stabilization of probe-target duplexes (ΔTm/modification up to +14.0 °C), provides the driving force for dsDNA recognition. In contrast, Z-modified Invaders show much lower dsDNA recognition efficiency. Thus, even very conservative changes in the chemical makeup of the intercalator-functionalized nucleotides used to activate Invader duplexes, affects dsDNA-recognition efficiency of the probes, which highlights the importance of systematic structure-property studies. The insight from this study will guide future design of Invaders for applications in molecular biology and nucleic acid diagnostics.

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Towards the Sequence‐Selective Recognition of Double‐Stranded DNA Containing Pyrimidine‐Purine Interruptions by Triplex‐Forming Oligonucleotides

Cited by 66 publications

References 143 publications

Synthesis of C-5, C-2′ and C-4′-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes

Synthesis of C-5, C-2′ and C-4′-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes

Recognition of mixed-sequence DNA using double-stranded probes with interstrand zipper arrangements of O2′-triphenylene- and coronene-functionalized RNA monomers

Recognition of double-stranded DNA using energetically activated duplexes with interstrand zippers of 1-, 2- or 4-pyrenyl-functionalized O2′-alkylated RNA monomers

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