Triplex-forming oligonucleotides (TFOs) can bind to polypurine/polypyrimidine regions in DNA in a sequence-specific manner. The specificity of this binding raises the possibility of using triplex formation for directed genome modification, with the ultimate goal of repairing genetic defects in human cells. Several studies have demonstrated that treatment of mammalian cells with TFOs can provoke DNA repair and recombination, in a manner that can be exploited to introduce desired sequence changes. This review will summarize recent advances in this field while also highlighting major obstacles that remain to be overcome before the application of triplex technology to therapeutic gene repair can be achieved.

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The potential for gene repair via triple helix formation.

The ability of cationic phosphoramidate pyrimidine alpha-oligonucleotides (ONs) to form triplexes with DNA duplexes was investigated by UV melting experiments, circular dichroism spectroscopy and gel mobility shift experiments. Replacement of the phosphodiester linkages in alpha-ONs with positively charged phosphoramidate linkages results in more efficient triplex formation, the triplex stability increasing with the number of positive charges. At a neutral pH and in the absence of magnesium ions, it was found that a fully cationic phosphoramidate alpha-TFO (triplex-forming oligonucleotide) forms a highly stable triplex that melts at a higher temperature than the duplex target. No hysteresis between the annealing and melting curves was noticed; this indicates fast association. Moreover, the recognition of a DNA duplex with a cationic alpha-TFO through Hoogsteen base pairing is highly sequence-specific. To the best of our knowledge, this is the first report of stable triplexes in the pyrimidine motif formed by cationic alpha-oligonucleotides and duplex targets.

Highly Stable DNA Triplexes Formed with Cationic Phosphoramidate Pyrimidine α-Oligonucleotides

Using an aryl phenanthroimidazole moiety as a conjugated flexible intercalator to improve the hybridization efficiency of a triplex-forming oligonucleotide

Synthesis and properties of oligo-2'-deoxyribonucleotides containing internucleotidic phosphoramidate linkages modified with pendant groups ending with either two amino or two hydroxyl functions.

Syntheses are described for two novel twisted intercalating nucleic acid (TINA) monomers where the intercalator comprises a benzene ring linked to a naphthalimide moiety via an ethynediyl bridge. The intercalators Y and Z have a 2-(dimethylamino)ethyl and a methyl residue on the naphthalimide moiety, respectively. When used as triplex-forming oligonucleotides (TFOs), the novel naphthalimide TINAs show extraordinary high thermal stability in Hoogsteen-type triplexes and duplexes with high discrimination of mismatch strands. DNA Strands containing the intercalator Y show higher thermal triplex stability than DNA strands containing the intercalator Z. This observation can be explained by the ionic interaction of the protonated dimethylamino group under physiological conditions, targeting the negatively charged phosphate backbone of the duplex. This interaction leads to an extra binding mode between the TFO and the duplex, in agreement with molecular-modeling studies. We believe that this is the first example of an intercalator linking the TFO to the phosphate backbone of the duplex by an ionic interaction, which is a promising tool to achieve a higher triplex stability.

Stability of Hoogsteen-type triplexes - electrostatic attraction between duplex backbone and triplex-forming oligonucleotide (TFO) using an intercalating conjugate

Synthesis of several α-oligonucleotides containing both anionic phosphodiester and cationic N-(dimethylaminopropyl)phosphoramidate internucleosidic linkages is described. Their ability to form triple helix with dsDNA was evaluated at various pH by UV melting experiments.

Alpha-oligonucleotides with anionic phosphodiester and cationic phosphoramidate linkages enhanced stability of DNA triple helix.

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Alpha-oligonucleotides with anionic phosphodiester and cationic phosphoramidate linkages enhanced stability of DNA triple helix.