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

Authors :
Watanabe, Seiji
Amporndanai, Kangsa
Awais, Raheela
Latham, Caroline
Awais, Muhammad
O’Neill, Paul M.
Yamanaka, Koji
Hasnain, S. Samar
Source :
Scientific Reports. 5/27/2024, Vol. 14 Issue 1, p1-18. 18p.
Publication Year :
2024

Abstract

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 SOD1G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1G93A mice clearly indicating functional improvement. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Volume :
14
Issue :
1
Database :
Academic Search Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
177940213
Full Text :
https://doi.org/10.1038/s41598-024-62903-5