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. The research is highlighted today (8th February 2006) in the flagship chemistry journal Angewandte Chemie.
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 drug agent, 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 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 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 the Barcelona team they found that it bound 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 Lawrence Young, from the University of Birmingham’s Division of Cancer Studies, says, ‘’Drugs that target DNA continue to be the mainstay of conventional anti-cancer therapy. Because three way junctions in DNA are a common feature of cancerous cells, this new research will be extremely helpful in allowing cancer researchers to develop drugs that act by specifically targeting cancer cells. This in turn should help reduce the unpleasant and unwanted side-effects of current treatments’.
The research is published in Angewandte Chemie and can be found at http://www3.interscience.wiley.com/cgi-bin/jhome/26737
Notes to Editors
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 Professor 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 Professor 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 the 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. High resolution pictures of the cylindrical shaped synthetic drug and the DNA 3-way junction are available by email from the Press Office. Please call Kate Chapple, Press Officer, 0121 414 2772 or 07789 921164.
5. 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.
For further information
Kate Chapple, Press Officer, University of Birmingham, tel 0121 414 2772 or 07789 921164.