Medical College of Wisconsin
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A synergistic small-molecule combination directly eradicates diverse prion strain structures. Nat Chem Biol 2009 Dec;5(12):936-46

Date

11/17/2009

Pubmed ID

19915541

Pubmed Central ID

PMC2909773

DOI

10.1038/nchembio.246

Scopus ID

2-s2.0-73549103148 (requires institutional sign-in at Scopus site)   89 Citations

Abstract

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.

Author List

Roberts BE, Duennwald ML, Wang H, Chung C, Lopreiato NP, Sweeny EA, Knight MN, Shorter J

Author

Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aniline Compounds
Catechin
Drug Synergism
Heat-Shock Proteins
Models, Chemical
Models, Molecular
Peptide Termination Factors
Phthalimides
Prions
Protein Conformation
Protein Folding
Saccharomyces cerevisiae Proteins
Small Molecule Libraries