If the hypothesis that the gain-of-function toxicity of SOD1 is triggered by a preferential increase in unfolded state population is correct, than one approach to mitigating the destabilization effect of disease-related mutations or zinc deficiency might be to use a small-molecule to preferentially stability the native state. We have developed a sensitive time-resolved FRET based assay (with a Zscore of 0.9) and used it with our custom automated time-resolved fluorescence instrument to identify approximately a dozen hits. Our goal is to continue optimization of these compounds and identify other compounds specifically from a CNS library.
