Progress towards drugs that protect brain cells

With the announcement that Parkinson’s UK have committed a further £1million to the Keapstone Virtual Biotech project, we go behind the scenes to learn more about the progress made.

Hidden away in some of the most sophisticated labs in the country, researchers are tweaking the structure of molecules that could, one day, be able to cure cancer, prevent dementia or maybe even slow Parkinson’s. This vital stage of the research pipeline aims to take ideas for potential treatments, and develop drug molecules that would be both safe and effective to take forward into clinical trials.

The starting point is normally a molecule that we know works in the right way. It may exist in nature, or be manmade, but often the effects of this first molecule are far too weak. The job of the chemistry specialists in these labs is to tweak the structure of the starting molecule, making minor alterations or substitutions, to find ways to make it more potent.

In some ways, it’s like playing with a sophisticated Lego set, where, instead of blocks, the researchers are combining atoms in different ways. And, to manipulate chemical structures, a great deal more safety equipment is required.

When it comes to designing a potential drug, you could come at it from many different angles. There often isn’t one answer when looking for a drug with a desired effect, as such researchers sometimes develop a range of different potential drug molecules in tandem.

Having several viable molecules means if one molecule is found to have an insurmountable issue, such as serious side effects, you still have other options. It also means that later on you can choose the molecule with the best effects.

A drug development project to slow Parkinson’s

Supporting drug development projects is an important part of producing new treatments. So, in March 2017, we launched a new £1million project with, Sheffield-based spin out company Keapstone Therapeutics. The project aims to develop drugs that combat oxidative stress and could halt brain cell death. This project was the first for Parkinson’s Virtual Biotech which fast-tracks the most promising scientific discoveries to rapidly develop and test treatments with the potential to transform life for people with Parkinson’s.

Our Drug Discovery Manager, Jan Kulagowski, gives us an update on progress so far.

Can you explain the project?

“The project started after a team of researchers at Sheffield University, led by Dr Richard Mead, identified a way to help protect brain cells in models of Parkinson’s and other neurodegenerative conditions. What they discovered was a way to protect cells from the damaging effects of oxidative stress.”

What’s oxidative stress?

“Our bodies constantly produce naturally occurring molecules called free radicals simply by using oxygen in order to live. Most of the time our bodies detoxify the free radicals that are produced to protect us from damage. But, left unchecked, these molecules can cause damage to our cells and tissues — this is called oxidative stress.”

“We’re particularly interested in the Nrf2 pathway, and potential drug molecules that interact with it. We believe it could be key to preventing oxidative stress and able to slow the loss of brain cells in Parkinson’s.”

Are there drugs that interact with Nrf2?

“Broccoli, especially as young sprouts, is a rich source of sulforaphane — a compound that has been shown to interact with the Nrf2 pathway. Unfortunately, there is no evidence that eating your greens has any effect on the progression of Parkinson’s. While sulforaphane is one of the reasons broccoli is meant to be good for us, it only has very weak activity — you would need something that is a lot more potent if you wanted to see substantial effects.

“The challenge is to find and develop molecules that work in a different way and have a stronger effect on the Nrf2 pathway, and demonstrate that they have enough potential to go forward into clinical trials. The good news is we have a molecule that is a good starting point and, over the last year, we’ve been working on improving its potency, making it even more effective.”

How have you been improving this drug molecule?

“By making small alterations to the structure of the molecule, we may see changes in how it works. They could be small or larger effects that either improve or reduce activity. Because it is hard to predict what effect a slight change may have, we have to produce lots of different molecules and test them.

“So far, we’ve been highly successful. By tweaking the molecule we have made it much better at interacting with the Nrf2 pathway. But it hasn’t all been plain sailing…”

What challenges have their been?

“When it comes to treating Parkinson’s, one of the key challenges is molecules need to be able to get into the brain.

“We know molecules with certain properties are more likely to get in the brain, but when we find a drug molecule with the right activity one of the problems is often converting it into something that can get into the brain. Fortunately, our initial starting molecule was already able to get into the brain, so we could focus on improving its effectiveness.

“When developing molecules to improve its potency you can risk reducing its ability to get into the brain. It’s a fine balancing act, and there’s still some more tweaking to be done, but our results so far are looking good.”

What are the next steps?

“Part of what makes the Virtual Biotech special is that our hands-on funding and management approach allows us to pick up projects and drive them forward, while staying flexible. If a project is not working out we can stop it and invest money in other areas.

“Obviously, we are very happy with how this project is going. That’s why we’ve just committed £950,000 over a further 9 months to continue developing drug molecules that target Nrf2. It’s been challenging but progress has been made. And we hope by the end of this funding round we may have a candidate molecule to take forward to pre-clinical testing, bringing us one step closer to clinical trials.”

How can people help?

“Like all our research, we wouldn’t be able to continue making progress without the support of people like you.

“From members of our Research Support Network — who guide our research and take part in studies that improve our understanding of Parkinson’s — to people who volunteer their time or donate to our research. Together, we can be a powerful movement for change, with everyone working together to improve life and find a cure.”