MX at Diamond aids drug development for motor neurone disease

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. 

Superimposed and individual crystal structures of A4V SOD1 bound with compounds. a Ebselen (pink) and compound 13 (yellow). b Compounds 2 (cyan) and 5 (pink). c Compounds 3 (cyan) and 6 (pink). d Compounds 9 (cyan) and 10 (pink). Surrounding amino acid residues of each monomers are coloured in purple and blue. Waters are represented as red dots. Hydrogen bonds are illustrated as green dashed lines. The distances between atoms and between aromatic rings are illustrated as yellow and black dashed lines, respectively.

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:  

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.