Finding the right partner is a tricky affair if the partner has to be a suitable one and the partnership endure. Chemistry and pharmaceutical researchers are also aware of this problem, for example, in their search for good binding partners for tumour associated proteins.

Success with antibodies

Up until now antibodies have been used as specific binders. As part of the immune system these big proteins bind various foreign particles and neutralise them. Because of their selective binding properties they are also used to treat cancer. Professor Dario Neri from the ETH Institute of Pharmaceutical Sciences (1) and his research team have succeeded in developing antibodies against the fibronectin ED-B domain. This domain is characteristic of growing blood vessels, such as those that occur in tumours. This means that tumours, in animals or in human beings, can be specifically marked. But that is not all; in mice models, for example, by coupling messengers that stimulate an immune reaction with ED-B binding antibodies, research shows that they can successfully attack tumours.

Disadvantages of antibodies

Does this mean that we forge ahead on the antibody track? Neri sees things somewhat differently. Despite all the success surrounding his current research with antibodies the scientist is aware of the disadvantages of treatments based on antibodies. It is widely known that a multiple administering of therapeutic antibodies can lead to an immune reaction against them Furthermore, their size inhibits their targeting of specific parts of the diseased cell.

Search for alternatives

So Neri is looking for an alternative method with the help of which he hopes to find much smaller molecules than antibodies, with similar binding strengths but without the disadvantages. In an article in the May issue of the professional journal "Nature Biotechnology" he and his team describe the new technology "ESACHEL", which stands for encoded self-assembling chemical libraries (2).

Cleverly combined

The principle of ESACHEL is that it couples small organic molecules of varying sizes with short strands of DNA, which contain both a conserved section and a section that serves to encode individual organic molecules.

By attaching small organic molecules (for example the red ball) to short strands of DNA scientists hope to find new and efficient binders. (Picture: D. Neri) large

In this way an entire library can be set up containing DNA molecules coupled with organic substances. What is decisive is the ability of the DNA sequences to build DNA duplexes (or even DNA triplexes) over the conserved sections. This allows scientists to combine libraries. When, for example, two libraries with 100 substances each are brought together, this already produces 10,000 combinations.

These combined molecules can then be tested to see whether they can produce the desired protein binders. If binding takes place the specific decoded sections provide information on which combination of organic molecules is responsible. For that purpose, DNA microchips are used that contain the counterpart to all possible individual DNA codes of the organic molecules. In a further step the identified organic molecules can then be coupled with a binder molecule. The obstacle that DNA poses when it comes to medical applications is thus overcome.

Proof of principle

Using two-fold model systems Neri and his team succeeded in isolating small organic molecules that bind themselves to those proteins that they need. The Functional Genomic Center Zurich was of great help, says Neri. As he explains, without the level of automation available at the center they would not have been able to produce the necessary substance libraries and analyse the binders with a reasonable amount of time and work.

"The big question now is whether we can isolate molecules that bind themselves to the proteins we are interested in," says the scientist, looking into the future. Should they succeed it would mean a leap forward in cancer treatment. Owing to their size they do not expect to see an immune reaction from the small molecules. Moreover, they should be able to infiltrate the cells, which would open the way for a wide spectrum of targets.