Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement

Sci Rep. 2024 May 27;14(1):12118. doi: 10.1038/s41598-024-62903-5.

Abstract

Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1G93A mice clearly indicating functional improvement.

Keywords: Amyotrophic lateral sclerosis; Drug development; Ebselen; Motor neuron disease; Riluzole; Superoxide dismutase; Target engagement.

MeSH terms

  • Amyotrophic Lateral Sclerosis* / drug therapy
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Animals
  • Azoles* / pharmacology
  • Disease Models, Animal
  • Humans
  • Isoindoles* / pharmacology
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Organoselenium Compounds* / pharmacology
  • Organoselenium Compounds* / therapeutic use
  • Superoxide Dismutase-1* / genetics
  • Superoxide Dismutase-1* / metabolism

Substances

  • Superoxide Dismutase-1
  • ebselen
  • Organoselenium Compounds
  • Isoindoles
  • Azoles
  • SOD1 protein, human
  • Neuroprotective Agents

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