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Issue 39, 2014
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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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Abstract

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 XZ 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.

Graphical abstract: 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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Publication details

The article was received on 09 Jun 2014, accepted on 04 Aug 2014 and first published on 13 Aug 2014


Article type: Paper
DOI: 10.1039/C4OB01183J
Citation: Org. Biomol. Chem., 2014,12, 7758-7773
  • Open access: Creative Commons BY license
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    Recognition of double-stranded DNA using energetically activated duplexes with interstrand zippers of 1-, 2- or 4-pyrenyl-functionalized O2′-alkylated RNA monomers

    S. Karmakar, A. S. Madsen, D. C. Guenther, B. C. Gibbons and P. J. Hrdlicka, Org. Biomol. Chem., 2014, 12, 7758
    DOI: 10.1039/C4OB01183J

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