Triplex-forming molecules: from concepts to applications

Faria, Marcella; Giovannangéli, Carine

doi:10.1002/jgm.192

Cited by 74 publications

(53 citation statements)

References 95 publications

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“…psoriasis. The present findings support the possibility that triplex-forming oligonucleotides together with other high affinity specific DNA-binding molecules, such as peptide nucleic acids and polyamides (16), may prove useful for the development of therapeutics and as tools for further understanding of DNA-associated functions in the cellular context.…”

Section: Discussionsupporting

confidence: 79%

“…A number of studies have reported TFO-associated activities in cell culture experiments including the modulation of gene expression and the induction of genomic modifications at selected sites (16). Triplex-mediated inhibition of transcription may be achieved by interfering with transcription initiation (competition of TFOs with transcription factors at the promoter) or by interfering with transcription elongation (RNA synthesis arrest at triplex structures).…”

mentioning

confidence: 99%

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Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

Besch

Giovannangéli

Kammerbauer

et al. 2002

Journal of Biological Chemistry

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Selected sequences in the DNA double helix can be specifically recognized by oligonucleotides via hydrogen bonding interactions. The resulting triple helix can modulate DNA metabolism and especially interfere with transcription in a gene-specific manner. To explore the potential of triplex-forming oligonucleotides (TFOs) as gene repressors, a TFO was designed to target a 16-bp sequence within the third intron of the human intercellular-adhesion molecule-1 (ICAM-1) gene, which plays a key role in initiating inflammation. TFO binding to its ICAM-1 target sequence was characterized in vitro and also demonstrated in cell nuclei with the set-up of a novel magnetic capture assay, which represents a general experimental approach to the detection of specific TFO binding and to the determination of the accessibility of a given genomic DNA locus. In a human keratinocyte cell line (A431), we observed that: (i) the ICAM-1 target sequence in the chromatin context within the nuclei is still available for triplex formation and (ii) TFO inhibits sequence and gene-specific interferon-␥-induced ICAM-1 surface expression. Collectively, the data demonstrate effective and specific inhibition of ICAM-1 expression by TFO treatment and support the view that triplex-mediated gene targeting might be a valuable technique for anti-inflammatory or anticancer strategies.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

Besch

Giovannangéli

Kammerbauer

et al. 2002

Journal of Biological Chemistry

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“…[9,10] TFOs are easily customizable and have a large library of potential target sites in mammalian genomes. [11] Parallel or antiparallel triplexes can be formed via Hoogsteen, or reverse-Hoogsteen hydrogen bonds, respectively, depending on the orientation of the TFOs relative to the homopurine strand.…”

Section: Introductionmentioning

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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“…131 Longer binding-site size is considered to be crucial for application in gene regulation since longer sequences should occur less frequently in genome leading to the development of various polyamide motifs for selective targeting. 132,133 The most promising strategy came from chemical ligation of two hairpin polyamides to form dimers. 134,135 However, though having an excellent affinity and specificity to 10 base pair (bp) DNA sequences, hairpin dimers lack the cell and nuclear uptake properties of smaller hairpins, apparently due to size and shape.…”

Section: Dna Minor Groove Templation Rolementioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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Triplex-forming molecules: from concepts to applications

Cited by 74 publications

References 95 publications

Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

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

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

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