Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).

backgroundCu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

methodsThe approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC RESULTS AND

conclusionsDimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand T