Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy

Chantadul, Varunya, Wright, Gareth SA ORCID: 0000-0002-3756-9634, Amporndanai, Kangsa, Shahid, Munazza, Antonyuk, Svetlana V ORCID: 0000-0002-2779-9946, Washbourn, Gina, Rogers, Michael, Roberts, Natalie, Pye, Matthew, O'Neill, Paul M ORCID: 0000-0003-4338-0317
et al (show 1 more authors) (2020) Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy. COMMUNICATIONS BIOLOGY, 3 (1). 97-.

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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.

Item Type: Article
Uncontrolled Keywords: Humans, Motor Neuron Disease, Sulfur Compounds, Organoselenium Compounds, Azoles, Molecular Chaperones, Crystallography, X-Ray, Drug Evaluation, Preclinical, Amino Acid Substitution, Protein Structure, Tertiary, Protein Folding, Drug Design, Mutation, Missense, Thermodynamics, Models, Molecular, Mutant Proteins, Isoindoles, Protein Multimerization, Protein Stability, Drug Discovery, Molecular Docking Simulation, Superoxide Dismutase-1
Depositing User: Symplectic Admin
Date Deposited: 12 May 2020 15:35
Last Modified: 18 Jan 2023 23:52
DOI: 10.1038/s42003-020-0826-3
Open Access URL: https://www.nature.com/articles/s42003-020-0826-3
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3087089