Dihydropyrimidine-Thiones and Clioquinol Synergize To Target β-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism.

ABSTRACT: The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer's disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity.

SUBMITTER: Tardiff DF 

PROVIDER: S-EPMC5705239 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature