Many people are aware that world-famous scientist Stephen Hawking suffered from amyotrophic lateral sclerosis (ALS) (also commonly known as Lou Gehrig's disease or motor neurone disease). ALS is a progressive neurodegenerative disease, in which damage to motor neurons leads to muscle weakness, paralysis and death. Prof Hawking's case was very unusual in its early onset and slow progression (he was 76 when he died). There are between 5,760 and 6,400 new diagnoses each year worldwide, and life expectancy for the average patient is two to five years after diagnosis. There is currently no cure for ALS, and only two treatments to slow down its progression - Riluzole, approved in 1995, and edaravone in 2017. Both of these drugs are expensive and not affordable for every patient.
In research recently published in EBioMedicine, researchers from the Universities of Liverpool and Nagoya used Diamond Light Source to investigate several novel compounds developed from a Selenium-based drug, ebselen. Their results suggest that these compounds are effective enough to progress to the next stage of drug development, with the aim of developing new ALS therapies that are both effective and affordable.
ALS is a neurodegenerative disease affecting around two people per 100,000 worldwide. It affects motor neurons in the brain and spinal cord, with symptoms progressing from muscle weakness to paralysis and death by respiratory failure. There is currently no cure, and we don't have a complete understanding of the causes of the disease. A mutation in the sod1 gene causes around 20% of familial cases. The mutant gene leads to the production of mutant SOD1 proteins. Whereas normal SOD1 proteins usually come together in pairs of molecules, the mutated protein cannot. The mutated proteins in single molecules are prone to aggregate and form toxic protein inclusions in neuronal cells resulting in the loss of motor neurons. One treatment option is, therefore, to develop drugs that stabilise the mutant SOD1 proteins and slow down this degenerative effect.
There are currently only two drugs approved for ALS treatment - riluzole and edaravone. They are expensive and have a limited effect, so new therapies are urgently required. However, the development of new drug molecules is a slow process, with very few potential candidates ultimately being approved for human use.
Using existing drug molecules as a template may help to speed up the process because some pharmacological and safety properties have already been investigated. Ebselen is a synthetic selenium-based drug with anti-oxidant and anti-inflammatory effects. It is considered to be a potential template for developing novel molecules that can stabilise SOD1 mutant proteins and protect motor neurons.
In this work, published earlier this year¹ the team developed next-generation ebselen-based compounds.
Macromolecular crystallography (MX) exploits synchrotrons to reveal the shape and arrangement of biological molecules at atomic resolution. MX is a core activity at Diamond with seven dedicated beamlines. For this research, the team used several of Diamond's MX beamlines (I03, I04, I04-1 and I24) to visualise how the new compounds stabilise the mutant SOD1 protein at the molecular level. This information is beneficial for the rational design of next generation compounds with better stabilising effects against mutant SOD1.
The researchers sent their samples to Diamond and performed their experiments remotely, rather than bringing them in person.
Lead author Dr Kangsa Amporndanai from the University of Liverpool explained why this is a more efficient process, she said:
Earlier in my research career, I and my colleagues used to drive with our samples for four hours from Liverpool to Diamond and sometimes the traffic made it longer! Now we can send the samples and carry out our experiments at Diamond by controlling from Liverpool, which is very time-saving. In the last few years, Diamond has offered a package of data-processing software that runs automatically while you are doing experiments at Diamond. It doesn't do all your work, but it analyses raw data quickly and guides a good way for your next experiments making your time at Diamond more efficient.
The target for these new drug compounds is the cysteine at position 111 (cys111) in the SOD1 protein. This solvent-exposed residue is vulnerable to oxidation that gives rise to aggregation. Ebselen-based compounds bind to this residue and enhance SOD1 stability. Results from in vitro studies show that these next-generation ebselen-based compounds are more effective than edaravone in protecting mouse neuronal cells. A transgenic ALS mouse model has demonstrated, for the first time, a delay in disease onset in vivo.
The team will continue working on these compounds. Although the development of new drugs is a long road, this is an important milestone in the development of new treatments for ALS.
Learn more about Macromolecular Crystallography at Diamond.
¹ Chantadul V et al. Ebselen as template for stabilisation of A4V mutant dimer for motor neuron disease therapy. Communications biology 3.1, 1-10 (2020). DOI:10.1038/s42003-020-0826-3.
Amporndanai K et al. Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis. EBioMedicine 59, 102980 (2020). DOI:10.1016/j.ebiom.2020.102980.
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