Sekikaic acid and lobaric acid target a dynamic interface of the coactivator CBP/p300.

Capturing a coactivator, naturally: the natural products sekikaic acid and lobaric acid, isolated after a high-throughput screen of a structurally diverse extract collection, effectively target the dynamic binding interfaces of the GACKIX domain of the coactivator CBP/p300. These molecules are the most effective inhibitors of the GACKIX domain yet described and are uniquely selective for this domain.

High-throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity.

Proteins with expanded polyglutamine (polyQ) segments cause a number of fatal neurodegenerative disorders, including Huntington's disease (HD). Previous high-throughput screens in cellular and biochemical models of HD have revealed compounds that mitigate polyQ aggregation and proteotoxicity, providing insight into the mechanisms of disease and leads for potential therapeutics. However, the structural diversity of natural products has not yet been fully mobilized toward these goals. Here, we have screened a collection of ~11 000 natural product extracts for the ability to recover the slow growth of ΔProQ103-expressing yeast cells in 384-well plates (Z' ~ 0.7, CV ~ 8%). This screen identified actinomycin D as a strong inhibitor of polyQ aggregation and proteotoxicity at nanomolar concentrations (~50-500 ng/mL). We found that a low dose of actinomycin D increased the levels of the heat-shock proteins Hsp104, Hsp70 and Hsp26 and enhanced binding of Hsp70 to the polyQ in yeast. Actinomycin also suppressed aggregation of polyQ in mammalian cells, suggesting a conserved mechanism. These results establish natural products as a rich source of compounds with interesting mechanisms of action against polyQ disorders.