Genetic way to make drugs more effective

Molecules that lock away unwanted sections of DNA, enabling drugs to work more effectively, have been discovered by research chemists at Warwick University in the English Midlands.

By locking DNA in tight coils, scientists could stop particular sequences activating biological changes that doctors would rather avoid or wish to regulate more effectively.

Until now, researchers trying to devise synthetic small molecules capable of binding to DNA have only been partially successful. Hitherto, the small molecules have only been able to stretch across a couple of DNA base pairs.

The University's Dr Mike Hannon and Dr Alison Rodger have produced a large synthetic molecule - called a supramolecular cylinder - that binds the major groove of DNA rather than the minor one.

When it binds, the synthetic molecule bends the particular section of DNA it is attached to. It becomes tightly coiled together in a manner resembling the way non-synthetic molecules package DNA together in chromosomes.

The ability of the synthetic molecule to coil up DNA could be used to lock up sequences so that they do not link with proteins to signal particular biological changes. This gives scientists new tools in gene regulation. It is presumed that the strong binding mechanism to the major groove will allow drugs to be delivered not only into the correct cell but into the nucleus as well.

The next task for the researchers will be to increase the sensitivity of the synthetic molecule to ensure its ability to bind specific DNA sequences more precisely. Currently, the molecule seeks out and stretches across a sequence of five DNA base pairs. It is hoped to extend the sequence to a 15 base pair sequence.

The supramolecular cylinder is an iron triple helicate with three organic strands wrapped around two iron centres to give it the cylinder shape that neatly fits within a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sections of DNA. The high positive charge of the cylinder also enhances its ability to bind to DNA that is negatively charged.

It has two mirror image forms (or enantiomers); the P enantiomer did still bind to the outside of the DNA's minor groove but its mirror image, the M enantiomer, preferred to bind inside the major groove.

For further information please contact Dr Michael Hannon