Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement

• Published in: Scientific reports 2024-05, Vol.14 (1), p.12118-12118, Article 12118
• Main Authors: Watanabe, Seiji, Amporndanai, Kangsa, Awais, Raheela, Latham, Caroline, Awais, Muhammad, O’Neill, Paul M., Yamanaka, Koji, Hasnain, S. Samar
• Format: Article
• Language: English
• Subjects: 631/154; 631/378; 631/535; 631/57; 692/308; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Azoles - pharmacology; Biochemistry; Biology; Complementation; Crystallography; Denervation; Disease Models, Animal; Drug development; Ebselen; Genes; Humanities and Social Sciences; Humans; Isoindoles - pharmacology; Life sciences; Medicine; Mice; Mice, Transgenic; Motor neurons; multidisciplinary; Mutation; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Organoselenium Compounds - pharmacology; Organoselenium Compounds - therapeutic use; Protein interaction; Proteins; Riluzole; Science; Science (multidisciplinary); Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Target engagement; Toxicity; Transgenic animals
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62903-5

Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein–ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1 G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1 G93A mice clearly indicating functional improvement.