Anti-prion compounds from marine invertebrates

Jennings LK1,2, Ahmed I3,4, Munn AL3,4 and Carroll AR1,2,5

  1. School of Environment and Science,.
  2. Environmental Futures Research Institute,.
  3. School of Medical Science,.
  4. Menzies Health Institute Queensland, Griffith University, Parklands Drive, Southport, QLD, 4222, Australia.
  5. Griffith Institute for Drug Discovery, Griffith University (Brisbane Innovation Park), Don Young Road, Nathan, QLD, 4111, Australia.

Prions (infectious protein folds) are the etiological agent of a number of neurodegenerative disorders characterised by an accumulation of misfolded forms of normal proteins as insoluble aggregates in the brain. The neurodegenerative diseases caused by prions are invariably fatal and there is a lack of curative treatments. Therefore, there is an urgent need to identify small molecules that have the ability to enter cells and cure prions. Screens using animals or cell lines infected by prions are expensive and time-consuming. However, the discovery that baker’s yeast (Saccharomyces cerevisiae) also harbours prions enables the use of yeast as a tool to facilitate the screen for anti-prion compounds. We have used two yeast prions [PSI+] and [URE3] to optimise previous high-throughput yeast-based anti-prion screens. This has enabled the application of such screens to natural extracts. We screened extracts from >500 marine invertebrates collected from temperate waters in northern NSW and identified 24 that cure yeast cells of the yeast prion [PSI+]. Of these, 6 extracts also cure the unrelated yeast prion [URE3]. Bioassay-driven chemical investigation of one of these 6 bioactive sponge extracts showed that a group of bromotyrosine derivatives were active. The active compounds in the other bioactive extracts have also been identified. Our findings highlight the value of a first stage screen of natural products using yeast strains infected with prions for the identification of chemically-diverse anti-prion compounds.