Article ; Online: Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.
Communications biology
2020 Volume 3, Issue 1, Page(s) 97
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 ... ...
| 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. |
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| MeSH term(s) | Amino Acid Substitution/genetics ; Azoles/chemical synthesis ; Azoles/chemistry ; Azoles/pharmacology ; Azoles/therapeutic use ; Crystallography, X-Ray ; Drug Design ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Isoindoles ; Models, Molecular ; Molecular Chaperones/chemical synthesis ; Molecular Chaperones/chemistry ; Molecular Chaperones/therapeutic use ; Molecular Docking Simulation ; Motor Neuron Disease/drug therapy ; Motor Neuron Disease/genetics ; Motor Neuron Disease/metabolism ; Motor Neuron Disease/pathology ; Mutant Proteins/chemistry ; Mutant Proteins/drug effects ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation, Missense ; Organoselenium Compounds/chemical synthesis ; Organoselenium Compounds/chemistry ; Organoselenium Compounds/isolation & purification ; Organoselenium Compounds/pharmacology ; Organoselenium Compounds/therapeutic use ; Protein Folding/drug effects ; Protein Multimerization/drug effects ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Sulfur Compounds/chemical synthesis ; Sulfur Compounds/chemistry ; Superoxide Dismutase-1/chemistry ; Superoxide Dismutase-1/drug effects ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism ; Thermodynamics |
| Chemical Substances | Azoles ; Isoindoles ; Molecular Chaperones ; Mutant Proteins ; Organoselenium Compounds ; SOD1 protein, human ; Sulfur Compounds ; ebsulfur ; ebselen (40X2P7DPGH) ; Superoxide Dismutase-1 (EC 1.15.1.1) |
| Language | English |
| Publishing date | 2020-03-05 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ISSN | 2399-3642 |
| ISSN (online) | 2399-3642 |
| DOI | 10.1038/s42003-020-0826-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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