Structure and Molecular Basis for Inhibiting Human SOD1 Aggregation by a Promising Decan Derivative Modulator: A Potential Therapeutic Strategy for Treating Amyotrophic Lateral Sclerosis (ALS)

Misfolding and aggregation of the human superoxide dismutase (hSOD1) protein are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a motor neuron disease. The structural stabilization and enzymatic activation of hSOD1 occur upon binding to Cu/Zn ions and forming an intramolecular disulfide bond. Mutations in hSOD1 result in structural changes in the electrostatic and metal-binding loops, leading to the dissociation of Cu and/or Zn ions, which in turn triggers SOD1 oligomerization in ALS. Through X-ray studies, we have identified 1,2,10-decanetriol, a solubilizing agent commonly used in drug delivery, as a modulator that binds at the electrostatic loop and dimer interface regions of SOD1. The crystal structure of hSOD1 complexed with 1,2,10-decanetriol, refined to 1.97 Å resolution, reveals that the ligand stabilizes both loop regions as well as the dimeric structure of hSOD1. Notably, this compound exhibits a low nanomolar binding affinity of 32.40 ± 0.65 nM for hSOD1 and significantly inhibits aggregation in both metalated and demetalated wild-type and disease mutant proteins. Among the various inhibitors investigated for their ability to reduce SOD1 oligomerization, our study is the first to identify a molecule that binds at the electrostatic loop, as confirmed by <i>in vitro</i> experiments. These findings suggest that 1,2,10-decanetriol is a promising scaffold with potential inhibitory properties for library development against SOD1's amyloidogenic behavior.