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

DOI: 10.1038/s42003-020-0826-3 DOI Help

Authors: Varunya Chantadul (University of Liverpool; Mahidol University) , Gareth S. A. Wright (University of Liverpool) , Kangsa Amporndanai (University of Liverpool) , Munazza Shahid (Lahore University of Management Sciences) , Svetlana V. Antonyuk (University of Liverpool) , Gina Washbourn (University of Liverpool) , Michael Rogers (University of Liverpool) , Natalie Roberts (University of Liverpool) , Matthew Pye (University of Liverpool) , Paul M. O’neill (University of Liverpool) , S. Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 3

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 15991 , 21970

Open Access Open Access

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.

Subject Areas: Medicine, Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Other Facilities: UoL Barkla X-ray laboratory

Documents:
s42003-020-0826-3.pdf