Targeting DNA with Triplexes

Abstract

The formation of intermolecular DNA triple helices offers the possibility of designing compounds with extensive sequence recognition properties which may be useful as antigene agents or tools in molecular biology. In these structures a third strand oligonucleotide binds in the DNA major groove, making specific contacts with substituents on the exposed faces of the base pairs. Although triplexes form with exquisite specificity their use suffers from several drawbacks. Two limitations of this approach, which are considered in this review are, firstly that conditions of low pH are necessary for formation of the C+*GC triplet, and secondly that these structures are often less stable than their duplex counterparts. This review outlines the strategies that have been employed to overcome these drawbacks. The pH problem is addressed by considering the various DNA base analogues that have been used to recognise GC base pairs in a pH independent fashion, and discusses the benefits and limitations of each analogue. Triplex stability can be increased by using novel base analogues, backbone modifications and the use of triplex-specific binding ligands.

DNA sequence specificity of triplex‐binding ligands

“…It can be seen that the T m of the second transition increases with increasing GC-content, as expected for melting of a DNA duplex, and is maximal for (CCT) 2 . In contrast the first melting transition is highest for (TC) 3 , consistent with the suggestion that regions of alternating C + GC and TAT triplets are unusually stable [40], and is similar to our previous work with intermolecular triplexes [38]. Figure 7 shows the effect of naphthylquinoline on these melting transitions and the DT m s induced by 10 lM ligand are shown in Table 2.…”

“…The most stable structures are formed when the stacked rings (bases or ligand) alternate between charged and uncharged species. Triplexes containing alternating C + GC and TAT triplets are not stabilized by ligands as they would interrupt the alternating pattern of charged and uncharged residues.Keywords: anthraquinone; molecular beacon; naphthylquinoline; triple helix; triplex-binding ligand.The formation of intermolecular DNA triple helices offers a means for designing agents which can bind to specific DNA sequences [1][2][3][4][5][6]. In this approach, a third strand oligonucleotide binds in the major groove of duplex DNA, forming specific hydrogen bond contacts with substituents on the purines of the duplex base pairs.…”

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

“…Several modifications of the sugar-phosphate backbone as well as of nucleotides have been developed to improve triple helix stability and specificity [45]. Another way to increase the stability of triplex consists in using ligands which bind selectively to triplex, shifting the equilibrium between duplex and triplex towards the latter [12].…”

Gold Nanoparticles Induce Apoptosis in MCF-7 Human Breast Cancer Cells

“…This multifunctionality opens the door to the possibility of new paradigms for cancer detection and treatment not previously considered possible. Nanoparticles have been increasingly used in biological and medical applications (Fox, 2000;Casey et al, 2001;Guntaka et al, 2003) including clinical diagnostics, therapeutics development and drug delivery, as well as advanced imaging. Meanwhile, effects of nanoparticles on health and safety have been also attracted more and more attention (Vasquez and Wilson, 1998;Guntaka et al, 2007).…”