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Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis

DOI: 10.1016/j.ebiom.2020.102980 DOI Help

Authors: Kangsa Amporndanai (University of Liverpool) , Michael Rogers (University of Liverpool) , Seiji Watanabe (Nagoya University; Nagoya University Graduate School of Medicine) , Koji Yamanaka (Nagoya University; Nagoya University Graduate School of Medicine) , Paul M. O'neill (University of Liverpool) , S. Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Ebiomedicine , VOL 59

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 21970

Open Access Open Access

Abstract: Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. Methods: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. Finding: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds.

Journal Keywords: SOD1; Ebselen; Drug design; Neurodegeneration; Motor neuron disease; COVID-19

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography


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