A new way of recognising DNA

Feb 16 2006

Scientists led by Mike Hannon at the University of Birmingham and Miquel Coll at the Spanish Research Council in Barcelona have discovered a new way that drugs can attach themselves to DNA, which is a crucial step forward for researchers who are developing drugs to combat cancer and other diseases.

DNA contains the information which encodes life itself; its double-helical structure was recognised 50 years ago. Scientists soon started designing drugs to target DNA and used them to treat diseases such as cancer, viral infections and sleeping sickness. In the 1960s, scientists discovered three different classes of clinical drug, each of which recognised DNA in a different way. Subsequent drugs have used only these three ways to recognise the DNA. Now the Birmingham and Barcelona teams have found a fourth which is completely different and opens up entirely new possibilities for drug design.

The scientists have developed a synthetic drug agent that targets and binds to the centre of a 3-way junction in the DNA. These 3-way junction structures are formed where three double-helical regions join together. They are particularly exciting as they have been found to be present in diseases, such as some Huntington’s disease and myotonic dystrophy, in viruses and whenever DNA replicates itself, for example, during cancer growth.

First of all, the Birmingham team created a nanosize synthetic drug in the shape of a twisted cylinder. Together with researchers in the UK, Spain and Norway they showed that is had unprecedented effects on DNA. Now molecular level pictures taken by the Barcelona team have shown that it binds itself in a new way to the DNA, by fixing itself to the centre of a DNA junction, which had three strands. It is all held together because the cylinder is positively charged and the DNA is negatively charged. In addition the drug is a perfect fit in the heart of the junction: a round peg in a round hole.

DNA is the genetic code in humans which carries all the information needed by our bodies in order to function properly. It is divided into units of genes. When a disease is present, genes are either working too hard or not enough, so to combat this, scientists are looking for ways to target those genes to turn them off or on or to make them work slower or faster. A number of current anti-cancer drugs target disease at DNA level, but they are not specific in their approach and this means that they can cause unpleasant side effects. Moreover some of these drugs suffer from developed resistance as the body learns how to deal with drugs that act in a particular way. By creating drugs which act in completely different ways this acquired resistance could be overcome.

Professor Mike Hannon, from the University of Birmingham’s School of Chemistry, says, ‘This is a significant step in drug design for DNA recognition and it is an absolutely crucial step forward for medical science researchers worldwide who are working on new drug targets for cancer and other diseases. This discovery will revolutionise the way that we think about how to design molecules to interact with DNA. It will send chemical drug research off on a new tangent. By targeting specific structures in the DNA scientists may finally start to achieve control over the way our genetic information is processed and apply that to fight disease’

Professor Miquel Coll’s team from the Spanish Research Council in Barcelona was able to obtain the molecular level picture of how the drug interacts with the DNA using a technique called X-ray crystallography at the European Synchrotron facility at Grenoble in France. Professor Miquel Coll says, ‘In 1999 we solved the structure of the four-way DNA junction -also called Holliday junction- which is how two DNA helices can ‘recombine’ (swop genetic information) and which is important in producing genetic diversity in humans and other organisms. But that junction was rather compact, without cavities or holes that could be used for drug binding. Now we have discovered that three-way DNA junctions are much more suitable for drug design: they leave a central cavity where a drug can fit perfectly and this opens a door for the design of new and quite unprecedented anti-DNA agents.’