| First Author | Watanabe S | Year | 2024 |
| Journal | Sci Rep | Volume | 14 |
| Issue | 1 | Pages | 12118 |
| PubMed ID | 38802492 | Mgi Jnum | J:348932 |
| Mgi Id | MGI:7644806 | Doi | 10.1038/s41598-024-62903-5 |
| Citation | Watanabe S, et al. (2024) Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement. Sci Rep 14(1):12118 |
| abstractText | 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. |
