7 September 2016

Danish research team revives drug research


As the first in the world, a Danish research team from the Department of Drug Design and Pharmacology has succeeded in mapping and producing two important substances which may greatly impact future drug research. A breakthrough that opens up completely new opportunities for developing and producing drugs. And a good example of interdisciplinary research providing good results, according to Professor Kristian Strømgaard, who is behind the new study.

Until now, no one had managed to crack the code. Not even an international competition offering a prize of USD 100,000 was incentive enough for researchers worldwide to figure out how to produce two unique and mysterious natural substances (YM, FR). The substances are important because they, along with only a handful of others, can inhibit a specific G protein in our cells. A mechanism that plays a major role in the development of modern drugs. As the first in the world, a Danish research team has now finally succeeded in developing and producing the two substances.

“This is a major breakthrough. Our new-found ability to produce these substances in a laboratory opens up a wealth of exciting opportunities within drug research. First and foremost, we’ve created a new ‘substance tool’ with huge potential within research. Moreover, we’re also able to produce different variants of the substances, which can further strengthen our research into targeting specific G proteins. In the long term, we can also examine whether the substances have relevance in relation to cancer research,” says Professor Kristian Strømgaard, Department of Drug Design and Pharmacology, Center for Biopharmaceuticals.

Thirty steps on the way towards the perfect substance
At cellular level, all drugs act from the outside to the nucleus of the cell. However, medical researchers are looking to refine this action so that the drug targets the relevant parts of the cell only, for example by blocking the so-called G protein. Today, researchers know of two natural substances that can do this. These substances are found in bacterial soups and plants, but the substances have so far not been available to a sufficient extent for researchers to be able to use them in their research.

“As a researcher, it’s frustrating to have knowledge of substances that we know are very important, without having access to them. We’ve now solved this problem, but it has been a long journey. It’s taken us two years to find out how to produce the two substances. The substances are highly complex, and it’s been a difficult process where we had to go through thirty steps in order to produce the substances,” says Kristian Strømgaard.

In addition to the production of the two substances, the research team has also succeeded in developing ten completely new variants, which may further provide researchers with insights into the biological effect of the substances. The researchers hope to be able to design substances in the long term that can, for example, impact on G proteins with cancer mutations.

Good example of interdisciplinary collaboration
The research project came into being when Professor Hans Bräuner-Osborne, who – like Kristian Strømgaard – is also from the Department of Drug Design and Pharmacology, encouraged Kristian Strømgaard and his research team, consisting of Assistant Professor Xiao-Feng Xiong and PhD Student Hang Zhang, to conduct research into how they could produce the substances. Over a two-year period, several SUND researchers helped the team crack the code. Postdoc Christina R. Underwood and PhD Student Mie F. Wöldike from Bräuner-Osborne lab performed the pharmacological studies, and Kasper Harpsøe and Associate Professor David Gloriam carried out molecular modelling to examine the structural context.  Finally, Thomas J. Gardella and Michael Mannstadt from Massachusetts General Hospital and Harvard Medical School in Boston performed the characterisation of a mutant and carcinogenic G protein.

“Apart from our discovery, this is a good example of what we can achieve when we work well together across disciplines. Hans Bräuner-Osborne came up with an issue that we found highly interesting and couldn’t wait to look into. He specialises in molecular pharmacology, whereas I’m from the chemistry side. Across our disciplines, we defined and solved a problem, which may have a major impact on future drug research,” says Kristian Strømgaard.

The study "Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors" is available here.

Contact: Professor Kristian Strømgaard, email: kristian.stromgaard@sund.ku.dk, mobile: +1 (857) 971-0097