Journal
NATURE CHEMICAL BIOLOGY
Volume 5, Issue 12, Pages 936-946Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.246
Keywords
-
Categories
Funding
- US National Institutes of Health (NIH) [2T32GM008275-21, DP2OD002177]
- Ellison Medical Foundation New Scholar in Aging Award
- American Heart Association
- University of Pennsylvania Institute on Aging and Alzheimer's Disease Core Center pilots
Ask authors/readers for more resources
Safely eradicating prions, amyloids and preamyloid oligomers may ameliorate several fatal neurodegenerative disorders. Yet whether small-molecule drugs can directly antagonize the entire spectrum of distinct amyloid structures or 'strains' that underlie distinct disease states is unclear. Here, we investigated this issue using the yeast prion protein Sup35. We have established how epigallocatechin-3-gallate (EGCG) blocks synthetic Sup35 prionogenesis, eliminates preformed Sup35 prions and disrupts inter- and intramolecular prion contacts. Unexpectedly, these direct activities were strain selective, altered the repertoire of accessible infectious forms and facilitated emergence of a new prion strain that configured original, EGCG-resistant intermolecular contacts. In vivo, EGCG cured and prevented induction of susceptible, but not resistant strains, and elicited switching from susceptible to resistant forms. Importantly, 4,5-bis-(4-methoxyanilino)phthalimide directly antagonized EGCG-resistant prions and synergized with EGCG to eliminate diverse Sup35 prion strains. Thus, synergistic small-molecule combinations that directly eradicate complete strain repertoires likely hold considerable therapeutic potential.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available