Effect of Quadruplex Ligands

Ligands that selectively bind to G-quadruplex structures may modulate telom-erase activity, alter telomere structure or repress the transcription of key oncogenes (for a review, see this book s chapters by M. Searle and J.F. Riou). The way ligands interact with quadruplexes also give clues on the dynamics of the G-quartets with the possible exception of a porphyrin derivative, true intercalation (between two quartets) is considered unfavourable or impossible. This indicates that, contrary to DNA base pairs, transient unstacking/opening of two G-quartets is an extremely rare or short event, incompatible with the incorporation of a planar chromophore. End stacking, which does not require the separation of two quartets nor the release of cation is therefore the most frequently observed mode of interaction.  

An important point concerning small quadruplex ligands would be to demonstrate that these molecules may not only bind to preformed quadruplexes, but also induce the formation of the multistranded structures starting from single strands. Kinetic analyses are well suited to answer to this question, as these modes of interactions should be reflected by differences in dissociation and association rates of the quadruplex, respectively. 

A perylene derivative called PIPER was the first example of a small ligand behaving as a driver in the assembly of quadruplex structures.Gel-shift experiments demonstrate that PIPER can dramatically accelerate the association of a DNA oligomer containing two tandem repeats of the human telomeric sequence (TTAG3) into di- and tetrameric G-quadruplexes. In 

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Data on the kinetics of bimolecular quadruplexes are scarce. Attachment of a long single-stranded tail to an oligonucleotide bearing two guanine blocks destabilizes and delays bimolecular quadruplex formation. This property has been used to determine the effect of quadruplex ligands on quadruplex forma-tion " " (see below). The second order rate constant for the formation of the bimolecular structure was estimated to be 3 x 10 M s in the absence of ligand. 

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