The Current Status of the ProblemChemical modification of triplex-forming oligonucleotides affects the stability of RNA triplexes. Incorporation of 2-omethayl-modified residues into triplex-forming oligonucleotides destabilizes and stabilizes triplex formation with duplex regions of RNA and DNA (Patterson, Plaxco, & Ricci, 2010). Impairment of RNA triplex formation may be facilitated by modulation of Van der Waals contact, pre-organization of the base stacking backbone, geometric compatibility, and dehydration energy (Patterson, Plaxco, and Ricci , 2010). Antisenses often consist of a very large number of mRNA molecules in a cell, and it is difficult to achieve complete inhibition of a specific mRNA. In addition to this, there are feedback mechanisms that can lead to increased mRNA production, in response to mRNA obliteration upon antisense therapy. Parallel triplexes are shown to be thermodynamically less stable at physiological pH (Patterson, Plaxco & Ricci, 2010). Two reasons explain the instability of the triplexes at pH 7 and above: the C+·GC triplet is stabilized by extension which only occurs at low pH and the juxtaposition of three polyanionic DNA strands is destabilizing at all pH values. (Patterson, Plaxco & Ricci, 2010). Another problem is that triplex-directed DNA recognition is strictly limited by the urinary polyp sequence, recognition of base pair inversions, in a duplex by chimeric TFOs, containing α-thymidine and α-deoxyguanosine (Patterson, Plaxco & Ricci, 2010). Hybridization of the hairpin with a set of chimeric probes proposes that double-stranded DNA recognition follows complex rules combining inverted Hoogsteen hydrogen bonds and non-canonical homologous hydrogen bonds. Molecules that bind to the DNA double helix can be...... middle of article ......chemistry, 82(21), 9109-9115. Reason for use: It describes the development therapeutic applications and functional genomics) Besch, R., & Degitz, K, 2004, Oligonucleotides forming triplex-sequence-specific DNA ligands as tools for gene inhibition and modulation of functions associated with DNA. Current Drug Targets, 5(8), 691-703. (Reason for use: Explains the state of transcription activity on the efficiency of triplex formation and binding and antigenic activity of a triplex-forming oligonucleotide conjugated to daunomycin) Guntaka, RV and Weber, K. T, 2003, Triplex-forming oligonucleotides as modulators of gene expression. The International Journal of Biochemistry and Cell Biology, 35(1), 22-31. (Reason for use: forms the basis of the scientific disciplines of molecular biology and genetics and underpins genomics, DNA diagnostics and modern aspects of forensic science.)