inherent specificity of base–base interactions, triplex formation is a versatile and powerful tool for sequence-
specific recognition of nucleic acids.
Studies on intermolecular triplex-forming oligonucleotides have been stimulated by their possible use
as therapeutic agents. This is known as the antigene concept of therapy, as described by Claude Hélène and
others.^51 A triplex-forming oligonucleotide(TFO) might be delivered to the nucleus of a cell to bind to a
unique sequence in the genome and so form a triplex and inhibit the transcription of a single gene or cleave
a specific site within a chromosome. For example, the ability to suppress the transcription of key genes
may trigger apoptosis in a cancer cell.
A major practical difficulty is the relatively low stability of triplex DNA compared to duplex structures
under physiological conditions. The presence of the third strand increases substantially the negative charge
near to the environment of the anionic duplex backbone. Therefore, relatively high cation (e.g.Naor K)
concentrations are required to stabilise the triple helix. Several approaches have been investigated to over-
come this problem, including the use of an intercalating ligand that can preferentially stabilize triplex DNA.
Duplexes and single-stranded DNAs can form triple helixes that have a number of different conform-
ations.52–54In one particular conformation, a third strand comprised of either cytosines or thymidines orien-
tates parallel to the polypurine strand of the duplex and binds to it through formation of Hoogsteen hydrogen
bonds (Figures 2.33 and 9.19). The resulting base triplets are T A–T and C G–C. Alternatively, the third
strand can be composed of purines, i.e.guanines or adenines that recognise and bind to the purine strand
of a target duplex to form T–A A or C–G G base triplets. The third strand binds in an antiparellel orienta-
tion with respect to the polypurine sequence and interacts with the duplex through reverse Hoogsteen
associations.
Reversible Small Molecule–Nucleic Acid Interactions 373
Figure 9.19 Hydrogen-bonding arrangement for two possible base triplets