Repurposing existing drugs to combat Parkinson’s

Therapy Breakthroughs 16. apr 2023 3 min Professor Daniel E. Otzen Written by Kristian Sjøgren

Researchers have screened 2,000 existing drugs and found 10 that could be effective against Parkinson’s disease. The drugs inhibit the harmful effects of small protein complexes that disrupt the brain cells in Parkinson’s.

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In the effort to develop drugs for diseases that are difficult to treat today, researchers do not always have to seek novel types of medicine. Sometimes they can also consider what has already been developed.

Researchers have now examined existing drugs and have identified 10 drugs that are effective in inhibiting one of the dominant molecular processes that are thought to lead to Parkinson’s.

The researchers’ next step is to determine whether these drugs can actually slow the development of Parkinson’s.

“We have started collaborating with colleagues to test the most promising of these drug compounds in some models for Parkinson’s. If we can validate our findings, this could open the way for later clinical testing,” explains the leader of the research team behind the study, Daniel Otzen, Professor at the Interdisciplinary Nanoscience Center (iNANO) and Department of Molecular Biology and Genetics, Aarhus University.

The research has been published in Chemical Science.

Parkinson’s disrupts brain cells

The researchers focused on one Parkinson’s disease characteristic in searching existing drugs for effectiveness.

In Parkinson’s, some of the brain’s cells slowly break down, resulting in the disease’s characteristic movement symptoms such as tremors, slow gait rigidity and rigidity.

The protein alpha-synuclein is a feature of Parkinson’s and appears to be the main culprit in disease development because mutations in the protein are associated with a considerably increased risk of developing Parkinson’s.

As Daniel Otzen explains, alpha-synuclein is a weird protein since it does not have any persistent structure of its own. Rather, it is very dynamic and preferably binds to membranes on the synapses in the brain and thereby helps them to transmit signals to each other. However, alpha-synuclein can also bind to other alpha-synuclein molecules, and this can cause problems.

“Thirty alpha-synuclein molecules can band together to form complexes called oligomers that can bind to various components in nerve cells. When oligomers bind to the cell membranes, they form a pore and disrupt the cell membranes, which results in neurodegeneration,” says Daniel Otzen.

Tested over 2,000 drug compounds for effects on oligomers

The idea behind the new research was very straightforward: to determine whether 2,067 drug compounds approved for various diseases could inhibit alpha-synuclein oligomers from disrupting cell membranes.

The researchers used a method of testing the compounds together with the oligomers on artificial cell membranes (vesicles) with a fluorescent substance inside.

If a drug is effective against the oligomers, it could theoretically inhibit the alpha-synuclein proteins associated with Parkinson’s from disrupting the cell membranes.

“Drug developers have intensely focused on repurposing existing drugs for new uses. This has many advantages, including knowing that the drugs are safe for human use and that the drugs can get through regulatory processes and reach patients much more rapidly,” explains Daniel Otzen.

Inhibiting oligomers

Lead author Arun Kumar Somavarapu painstakingly examined all 2,067 approved drug compounds. The researchers only selected compounds that could reduce the amount of fluorescent light emitted to less than 15% of the amount for controls. Most had no or very little effect on the oligomers, but there were a few promising hits. Of the 2,067 approved compounds, the researchers identified 10 that inhibited the alpha-synuclein oligomers from disrupting the cell membranes and that could therefore possibly be effective against Parkinson’s.

The researchers then examined the compounds for how they affected the oligomers. Some inhibited the oligomers from binding to the cell membranes, and others inhibited the oligomers from disrupting them.

“Although we identified several compounds that could be useful, we cannot allow patients to use them immediately. Some have not been approved for use in the brain at all, whereas others are antiseptic and have been developed for skin infections. The challenge is also whether these compounds are specific enough or whether they bind to many other parts of the cells in the brain or in other tissue that we do not want them to target,” says Daniel Otzen.

Testing drug candidates on mini-brains

The researchers will continue their studies to elucidate whether the drugs identified act on the oligomers in a more realistic set-up. They will use organoids: small mini-organs developed based on human cells produced by other researchers at Aarhus University.

“We need to test the drug candidates on brain organoids, which are designed to look like a Parkinson’s brain and slowly deteriorate as they age. We will then determine whether the compounds inhibit this deterioration. If they do, this can create a basis for proceeding to further study the potential of the various drugs. This applies not only to developing drugs targeting Parkinson’s but also for other diseases involving toxic oligomers,” concludes Daniel Otzen.

Drug repurposing screens identify compounds that inhibit α-synuclein oligomers’ membrane disruption and block antibody interactions” has been published in Chemical Science. The research was also supported by the Lundbeck Foundation and the Independent Research Foundation Denmark. In 2017, the Novo Nordisk Foundation awarded a grant to Daniel Otzen for the project Specific Binders Crossing the Blood–brain Barrier to Diagnose and Combat Parkinson’s Disease. 

Our research activities fall within 3 main areas: membrane protein folding, protein-detergent interactions and protein fibrillation. In all cases, we...

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