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- Title
Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.
- Authors
Chantadul, Varunya; Wright, Gareth S. A.; Amporndanai, Kangsa; Shahid, Munazza; Antonyuk, Svetlana V.; Washbourn, Gina; Rogers, Michael; Roberts, Natalie; Pye, Matthew; O'Neill, Paul M.; Hasnain, S. Samar
- Abstract
Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template. Chantadul et al. uses x-ray crystallography and differential scanning fluorescence-based assay to show that ebselen and its analogues increase thermostability of both WT and A4V mutant SOD1 when second free cysteine is removed using a point mutation. Hence, ebselen can be used as a template for structure based drug development of ALS therapeutics.
- Publication
Communications Biology, 2020, Vol 3, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-020-0826-3