University of Groningen scientists have demonstrated how to speed up drug development using well-known generic techniques. By creating a protective wrap (called an aptamer) from RNA, they managed to selectively modify groups of an aminoglycoside antibiotic. Using standard chemical synthesis, it would take about two years to design and perform all the necessary steps for this modification. The new technique takes just two to three months. The results were published online by the journal Nature Chemistry on 22 July.
Natural products are often complex molecules and are an increasingly important resource in lead structures for the pharmaceutical industry. In order to make them safe for medical use, however, or to optimize their functioning, they usually have to be modified. This modification process often requires laborious and cumbersome chemical procedures. It can take many months or even years to design the correct method to make the required modifications. ‘When you are investigating dozens of drug candidates, you can’t invest that much time in each interesting molecule’, says Professor Andreas Herrmann, lead investigator of the paper.
Herrmann decided to take a different approach. Aminoglycoside antibiotics are known to bind to RNA, a polymer very similar to DNA. This RNA molecule wraps around the aminoglycoside molecule, leaving only a small part exposed. ‘You can make new antibiotics by adding chemical groups to the aminoglycoside scaffold’, explains Herrmann. The backbone has several amino groups that could be modified. ‘But you don’t want to modify them all. So you have to find a way to protect most amino groups while modifying the group you’re targeting.’ The RNA wrap does just that.
‘We’ve shown that with the RNA wrap, we can selectively modify two sites on the aminoglycoside structure, resulting in new active antibiotics. And we can do this in just one step. Getting the same result via a chemical procedure would require 24 separate steps’, Herrmann explains. ‘This makes our procedure much faster, which could revolutionize drug development. It also enables us to make modifications that are too complicated for standard chemical methods.’
The new method is generic as RNA will bind to many complex molecules. And there is already a technique to quickly produce selectively binding RNAs, developed over fifteen years ago. This process, called SELEX (systematic evolution of ligands by exponential enrichment), starts with a mixture of about a trillion different RNA molecules. These are added to a target molecule, and all non-binding RNA is removed. The remaining RNA is amplified and again allowed to bind to the target molecule, but under more stringent conditions. By repeating this process several times, the RNAs with the strongest bonds are selected. The sequences of these RNAs can be read just like a DNA sequence. With this information, a large variety of the binding RNAs can be generated. These can then be used as wraps to modify the target molecules.
‘It is possible to make large quantities of RNA to do this kind of work’, explains Herrmann. ‘So we can make up to a gram of any modified molecule using the RNA wraps.’ This is enough for basic testing of potential drugs, and even early stage animal and clinical experiments. And all this in a fraction of the time needed to develop and produce these modified molecules by standard chemical techniques.
The University of Groningen research group is now working on ways to scale up the production of aptamers. ‘We are testing whether we can use DNA instead of RNA because it is about ten times cheaper. And we are looking for ways to reuse the wraps.’ Plans are under way to delegate part of this work to a start-up company. Herrmann’s research is mostly aimed at making novel materials using DNA or RNA, as part of the Zernike Institute for Advanced Materials, a research centre at the University of Groningen. ‘That’s why we have facilities to produce grams of RNA or DNA. Molecular biologists use minute quantities in comparison.’
Yesterday, a team of RUG students won the European Rover Challenge in Poland, a three-day competition in which student teams from all over the world compete.
BirdEyes is the Centre for Global and Ecological Change initiated by, among other partners, FSE and Campus Fryslân
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