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New tool makes it easier to decipher the communication system of cells

Researchers at the University of Copenhagen played a key role in the development of a method for tailoring drugs to combat a broad range of diseases.

If you need a drug to regulate specific biochemical signals to the body’s cells, you need to know what the cells’ receptors look like – how the cells receive the biochemical information you expect to affect a disease, such as a specific type of cancer.

The only problem is that it is extremely difficult to identify the cells’ receptors.

However, an international research team, headed by Professor David Gloriam of the Department of Drug Design and Pharmacology, at the University of Copenhagen, has now made this analysis much easier.

They have designed an internet-based tool for the free use of researchers all over the world. A total of ten scientists are behind the discovery, which is funded by the European Research Council and the Lundbeck Foundation, among others. Five are from the University of Copenhagen and the remaining five are from universities in Switzerland, China and the USA – and their discovery was recently published in the scientific journal Nature Methods.

To put it very simplistically, using this internet-based system, drug designers can identify the cells’ receptors significantly faster than they could with previous methods. Using the new system, they can generate a 3D image of these receptors – down to single-atom level. Professor David Gloriam explains:

‘Generating a 3D image of the so-called receptors – which, in reality, are receptor proteins embedded in the cell wall – takes many years, and only a few research groups are able to handle this process today. The new method could save many years of work in the lab – and also make it possible for a lot more scientists to generate 3D images of these receptor proteins. And the more 3D images we have of these proteins, the easier it will be to design drugs to combat a wide range of diseases.’

Many have not yet been mapped

The receptors David Gloriam and his colleagues are investigating are known in medical literature as G protein-coupled receptors (GPCR).

Human beings have about 800 different GPCRs which help carry information to various types of cell around the body. And a great many of the signals come from the brain.

Consequently, GPCRs are extremely important in the field of drug design. They are so important that around a third of all drugs work on these receptors.

However, although we are familiar with all of the GPCRs in the human body, in a way we do not really know them at all.

This is because the protein structure represented by each GCPR has, as yet, only been mapped for around 60 of the total 800 receptors.

‘And it’s precisely this mapping process that our system can help speed up,’ says David Gloriam, who is also a Lundbeck Foundation Fellow:

‘If a drug designer wants to work with a specific receptor, our system can provide a 3D image of it faster than any previous method.’

The new system does not create the 3D image itself but it is able to design the experiment that will give the final result.

The internet-based system generates a ‘stable’ image of the receptor(s) the scientists wish to decipher. And once this is done, the actual 3D image – which contains information down to single-atom level – can be produced by cryo-EM, among other methods.

When David Gloriam and his colleagues attempt to design drugs to influence one or more of the human G protein-coupled receptors, they are usually aiming to block signals to specific cells.

However, he explains that the strategy can also be applied in reverse: ‘In some cases, the intention may be to ensure that specific signals reach certain cells.’

FACTS:
Drugs and receptors

Beta blockers and antihistamines are examples of drugs which block G protein-coupled receptors. On the other hand, a number of painkillers – including opioid preparations – activate these receptors.

The five scientists from the Department of Drug Design and Pharmacology at UCPH who were involved in the development of the new method are: Christian Munk, Vignir Isberg, Louise F. Nikolajsen, Janne Bibbe and Professor David Gloriam.

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