Rational design of a triple helix-specific intercalating ligand

Escudé, Christophe; Nguyen, Chi Hung; Kukreti, Shrikant; Janin, Yves L.; Sun, Jian‐Sheng; Bisagni, Émile; Garestier, Thérèse; Hélène, Claude

doi:10.1073/pnas.95.7.3591

Cited by 107 publications

(77 citation statements)

References 37 publications

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“…A promising class of H-DNA-modulating agents includes DNA minor groove binders or intercalators which can bind to triplex structures. While minor groove binders typically destabilize triplexes, intercalators often stabilize this conformation by providing an aromatic surface area for stacking with triplex bases in an intercalation complex [161]. Most of these compounds were evaluated on intermolecular triplex structures, however, such molecules have the potential to modulate H-DNA as well, and it will be of interest to evaluate them on H-DNA structures.…”

Section: Stabilizing H-dnamentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

246

189

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DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a longstanding goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplexrelated gene targeting strategies for biotechnological and potential clinical applications.

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Section: Stabilizing H-dnamentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

246

189

View full text Add to dashboard Cite

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“…Recently we described the properties of pentacyclic benzoquinoloquinoxaline (BQQ) and benzoindoloquinoline (BIQ) that also produce a high stabilization of triplex structures. [21,22] In particular BQQ exhibited a high selectivity for the triplex compared with the corresponding duplex. [21] Linear dichroism experiments have provided evidence that benzopyridoindole derivatives intercalate between the base triplets of the triple helix.…”

Section: C3mentioning

confidence: 96%

“…[21,22] In particular BQQ exhibited a high selectivity for the triplex compared with the corresponding duplex. [21] Linear dichroism experiments have provided evidence that benzopyridoindole derivatives intercalate between the base triplets of the triple helix. [23] DT m measurements reported in the present work do not address the question of the structure of the complexes formed by dibenzophenanthroline derivatives.…”

Section: C3mentioning

confidence: 96%

Stabilization of DNA Triple Helices by Crescent-Shaped Dibenzophenanthrolines

et al. 1998

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Mono-and disubstituted crescent-shaped dibenzophenanthrolines have been prepared and their ability to stabilize synthetic DNA triple helices has been investigated. Thermal denaturation experiments were conducted on two triplexes of different sequences in the presence of the various compounds. For both targets, the monosubstituted derivatives (4 a,b) induced a large and specific increase of the temperature of the triplex-to-duplex transition compared with the duplex-to-single strand transition (DT 332 m À DT 231 m up to 32 8C), and appeared to be more efficient than their disubstituted analogues. Therefore compounds 4 a and 4 b seem to be better triplex-specific ligands than the previously reported benzopyridoindole (BPI) derivatives.

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“…It has been demonstrated that acridine, benzo(e)pyridoindole [44] or other similar intercalators [45] are able to stabilize parallel triplexes. Moreover, benzo(e)pyridoindole derivatives were able to induce formation of a triple helix even with an antiparallel GT-TFO, which was not formed in the absence of the ligand.…”

Section: Discussionmentioning

confidence: 99%

Triplex‐Forming Twisted Intercalating Nucleic Acids (TINAs): Design Rules, Stabilization of Antiparallel DNA Triplexes and Inhibition of G‐Quartet‐Dependent Self‐Association

2011

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The majority of studies on DNA triple helices have been focused on pH-sensitive parallel triplexes with Hoogsteen CT-containing third strands that require protonation of cytosines. Reverse Hoogsteen GT/GA-containing antiparallel triplex-forming oligonucleotides (TFOs) do not require an acidic pH but their applicability in triplex technology is limited because of their tendency to form undesired highly stable aggregates such as G-quadruplexes. In this study, G-rich oligonucleotides containing 2-4 insertions of twisted intercalating nucleic acid(TINA) monomers are demonstrated to disrupt the formation of G-quadruplexes and form stable antiparallel triplexes with target DNA duplexes. The structure of TINA-incorporated oligonucleotides was optimized, the rules of their design were established and the optimal triplex-forming oligonucleotides were selected. These oligonucleotides show high affinity towards a 16 bp homopurine model sequence from the HIV-1 genome; dissociation constants as low as 160 nM are observed whereas the unmodified TFO does not show any triplex formation and instead forms an intermolecular G-quadruplex with T(m) exceeding 90°C in the presence of 50 mM NaCl. Here we present a set of rules that help to reach the full potential of TINATFOs and demonstrate the effect of TINA on the formation and stability of triple helical DNA.

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Rational design of a triple helix-specific intercalating ligand

Abstract: DNA triple helices offer new perspectives toward oligonucleotide-directed gene regulation. However, the poor stability of some of these structures might limit their use under physiological conditions. Specific ligands can intercalate into DNA triple helices and stabilize them.

Cited by 107 publications

References 37 publications

DNA triple helices: Biological consequences and therapeutic potential

DNA triple helices: Biological consequences and therapeutic potential

Stabilization of DNA Triple Helices by Crescent-Shaped Dibenzophenanthrolines

Triplex‐Forming Twisted Intercalating Nucleic Acids (TINAs): Design Rules, Stabilization of Antiparallel DNA Triplexes and Inhibition of G‐Quartet‐Dependent Self‐Association

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