Researchers at the Universities of Liverpool (UK) and Nagoya (Japan) have demonstrated that a Selenium-based therapeutic, called ebselen and several other novel compounds developed at Liverpool, can change many of the toxic characteristics of a protein, superoxide dismutase (SOD1), which can cause Amyotrophic lateral sclerosis (ALS) or motor neuron disease. The study is published in the journal EBioMedicine.
ALS is a neurodegenerative disease that affects motor neurons and the neuronal links between our brain and our muscles. Eventually, nerve links die, and the patient becomes paralyzed, with the majority dying within 2 to 5 years of diagnosis. Roughly 20% of the familial ALS cases arise from dominant mutations in the sod1 gene. Aggregation of mutant SOD1 protein in cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017, remain the only drugs with limited therapeutic benefits.
A key strategy to avoid aggregation is to maintain the stabilization of the original SOD structure. The research team has developed several ebselen-based compounds with improvements in SOD1 stabilization and in vitro therapeutic effects with significantly better potency than edaravone. The structure-activity relationship of hits has been guided by high-resolution structures of ligand-bound A4V SOD1, a mutant that causes the most severe disease. They were also able to demonstrate disease onset delay of ebselen in a transgenic ALS model mouse, showing promise for therapeutic compounds.
Professor Samar Hasnain, international team lead, said, "The fact that this new generation of organo-selenium compounds have better in vitro neuroprotective activity than edaravone holds a significant promise for the potential of this class of compounds as an alternative therapeutic agent for ALS treatment.” He continued, “The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including the main protease of SARS-Cov-2 (COVID-19)."
Professor Paul O'Neill, leader of the medicinal chemistry program, said, "Our medicinal chemistry approach, guided by protein-ligand crystallography studies, focused on the design of ebselen based analogs that have improved in vitro potency coupled with excellent predicted CNS exposure and improved solubility and metabolic stability characteristics. By employing this multi-parameter optimization approach to drug design, the next key stage will be to screen our next-generation compounds in appropriate disease models."