Ligands specific for cancer-linked DNA structures are among a series of compounds that could help scientists trying to understand why DNA folds into squares.

G-Quadruplexes occur naturally in nucleic acids, and are formed as four guanine residues assemble in a planar arrangement. Now, a group led by Shankar Balasubramanian at the University of Cambridge, UK, has synthesised ligands that bind to these structures selectively. 

Balasubramanian's group used a class of compounds called triarylpyridenes as the template for designing its ligands, and varied the aromatic groups attached to the central pyridine structure. The compounds' interactions with different DNA structures were studied and some compounds were found to show definite selectivity for a G-quadruplex in a telomere - a repeat sequence at the end of a DNA strand. 

G-quadruplexes are formed when four guanine residues assemble into a square

Telomeric G-quadruplexes are involved in cell replication and death and often implicated in cancer cells' immortality. They are potential anticancer targets, and ligands that interfere with telomere maintenance are the subject of much research. 

Jörg Hartig from the University of Konstanz, Germany, who works on using quadruplexes to regulate nucleic acid function is impressed with the work, and the specificities for distinct quadruplex sequences. 'In addition to their potential in cancer therapy, the triarylpyridenes could enable researchers to specifically address one quadruplex structure while leaving other G-rich sequences unaffected,' he said.

'Molecules that bind selectively to these DNA motifs will help us understand G-quadruplex function in cells,' explained Balasubramanian. He added that the group will now evaluate its compounds to determine how they affect cellular processes.

Balasubramanian suggested that there may be thousands of G-quadruplex forming motifs in cells, all ever so slightly different. Looking to the future, the chemists see their challenge in designing molecules that discriminate between the quadruplexes well enough to allow the function of each quadruplex to be investigated individually.

Laura Howes