Breakthrough In The Design Of New Drugs - New Way Of Recognising DNA

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.'


1. DNA holds the human genetic code. To express this information, DNA copies itself into RNA, which holds exactly the same information. The RNA molecules create proteins which have a specific job to carry out, for example, they can be enzymes. To combat disease drug targets can be developed to work with DNA, RNA or proteins. For scientists, it is easier to target DNA, as only one molecule of the drug target is needed.


2. This work is part of a trans-European collaborative effort led by Prof. Mike Hannon, leader of the Birmingham research team and based around the agents developed by that team. The consortium which is funded by the European Commission Framework research programme involves research teams at: CSIC Barcelona, Spain; Chalmers University, Gothenburg, Sweden; Bergen University, Norway, University of Barcelona, Spain; Institute of Biophysics, Brno, Czech Republic. The work is focused on designing and studying the DNA binding of synthetic agents that are similar in size to the agents biology uses to recognise DNA. The team leader at CSIC Barcelona is structural biologist Prof. Miquel Coll.


3. The three previous modes of DNA recognition used by drugs are:


a. Slotting in between the DNA base pairs at the heart of the DNA (usually described by scientists as "intercalation"). This is like a sandwich with the DNA bases being the bread and the drug being the filling. An early example of such a drug used to treat cancer was doxorubicin (trade name 'Adriamycin' or 'Rubex'). This drug, launched in the 1960s, gave much impetus to the field and has been followed by a number of varients. This 'intercalation' binding mode was recognized in the early 1960s. Doxorubicin is classified by clinicians as an "anthracycline antiobiotic."


b. Binding in the grooves which are formed as the DNA strands wrap about each other to form the spiral (double-helical) structure. Examples of such drugs include berenil and stilbamidine, pentamidine. This mode of binding had been recognized in the late 1960s; some of the drugs were in the clinic by this time.


c. Forming direct bonds to the DNA bases that hold the genetic information and causing distortions to DNA structure. This mode of action is used by the platinum drugs that are among the most widely used anti-cancer agents in clinic today. The original platinum drug cis-platin (marketed as 'platinol') was discovered in the mid 1960s when its mode of DNA-binding was first established. It was introduced into the clinic in the 1970s. Three further platinum drugs (carboplatin - trade name 'Paraplatin', nedaplatin and most recently oxaliplatin - trade name Eloxatin) are also in clinical use. Clinicians refer to this general group of chemotherapy drugs as alkylating agents.


4. The journal Angewandte Chemie is the highest impact, primary-research Chemistry journal in the world. It has judged this work so important that it has not only assigned the paper VIP status (Very Important Paper), but also elected to feature the work on its front cover and has commissioned a 'Highlight article' (from a leading player in the field of DNA recognition and metal-based drugs: Professor B. Lippert of the University of Dortmund) to be positioned at the start of the journal issue to place the work in context and underline its importance.


Peer reviewed publication and references

Angewandte Chemie


UNIVERSITY OF BIRMINGHAM

Edgbaston

Birmingham

B15 2TT

UK


The University was founded in 1900 by the citizens of Birmingham who wanted their own university to train and educate the people who would create and manage the burgeoning businesses and industries of the midlands.


bham.ac.uk


View drug information on Eloxatin.