Finding drugs to treat dementia

09 July 2019

Interview with 

John Skidmore, ALBORADA Drug Discovery Institute

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Treating Alzheimer’s is a difficult thing. Often by the time you know the diagnosis, a lot of the damage has been done. So the emphasis is currently very much on preventing or slowing down the progression of the disorder. And drug developers are looking for drug molecules that can do that. Adam Murphy spoke to John Skidmore, from the ALBORADA Drug Discovery Institute in Cambridge, to learn about the work they do...

Adam - At the moment we can't cure Alzheimer's but that isn't going to stop people trying. John Skidmore at the Alborada Drug Discovery Institute in Cambridge is working to find ways of treating, and perhaps even curing the disease. But how do you go about doing what's eluded so many...

John - These days drugs are either small molecules which typically have perhaps about 70 atoms, or large biomolecules that might be 2 or 300 times bigger than that, we're finding small molecules. The reality of drug discovery is that we're still not good enough to sit down and use computers to design the drug from scratch. So we have to go about it in an interactive way where we make a series of potential molecules, look at their properties, and then try to improve them with the next round of molecules, and over a period of weeks and months we get better and better.

These small molecules are interacting with a particular protein in the body that we've identified as having a role in the disease. So the first thing we do is to take a big library of molecules, perhaps a couple of hundred thousand, and look to see whether we can find some that interact at any level with that protein.

Adam - With so many proteins and so many potential molecules to choose from, how do you even begin?

John - Well, that's the difficult thing actually. Sometimes if you have a crystal structure of that protein, you might be able to what we would say rationally design something. So perhaps you know a little bit about how the protein works and you can build it from first principles, in the way that you might design a car. But in lots of other cases, we simply don't know what the molecules are going to like at all and so you have to go back to screening. The library we have is as diverse as we can make it. It has as many different types of chemical structures as we can find and so it represents lots of potential start points.

Adam - What are these molecules going to do though? When you've found something, how is it going to help?

John - In terms of the drugs we're developing, we have to go back to the observations that the basic scientists are making. And really the science points to the fact that in Alzheimer's and, indeed, lots of other diseases that cause dementia there are mis-folded proteins in the brain. In Alzheimer's in particular, we have beta-amyloid and we've got a protein called tau.

Now, in fact, amyloid has been the focus over the last 15 or so years and it hasn't been all that successful. We know that the protein tau, which also mis-folds and aggregates, is sort of further down the disease progression. And so if we could find ways of changing the behaviour of tau, then that might be a way in which we could change the course of Alzheimer's disease.

What we'd really like to do is to reduce the mis-folded form of tau and we have a number of ideas about how we can remove that mis-folded protein. The body and cells have got mechanisms in place for clearing mis-folded proteins, and we've got ideas about how we can increase those processes in order to try to clear proteins such as tau, but also other proteins that cause other neurodegenerative diseases.

Adam - And what stage are you at with things here?

John - We've got a couple of really exciting projects that are looking at different ways of clearing these proteins. One of them is designed to increase a process called autophagy, and what autophagy does is it surrounds the clumps of mis-folded proteins with a membrane and then is able to destroy the materials that's within that membrane. Working with our collaborator, Professor David Rubenstein here at the University of Cambridge, we've identified a signalling molecule that can turn on autophagy and also a process by which an enzyme can remove that signalling molecule. And so the idea is if we can block the enzyme that removes the signalling molecule then we’ll see an increase in the signalling molecule, an increase in autophagy, and we'll start to clear the mis-folded proteins. And we've now got molecules that are able to interact with that enzyme at very low concentrations, which is what you need to be able to give something as a drug, and we are in the process of testing them. We've done lots of experiments in cells, we've got some very exciting data, and I think we going to be moving those molecules into animal models in the coming months.

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