title: A synergistic small-molecule combination directly eradicates diverse prion strain structures.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: Blake E
authors.initials: BE
authors.lastname: Roberts
authors.forename: Martin L
authors.initials: ML
authors.lastname: Duennwald
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Chan
authors.initials: C
authors.lastname: Chung
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lopreiato
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sweeny
authors.forename: M Noelle
authors.initials: MN
authors.lastname: Knight
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D010454:Peptide Termination Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D010797:Phthalimides / Q000494:pharmacology*; D011328:Prions / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: C545727:4,5-bis(4-methoxyanilino)phthalimide; D000814:Aniline Compounds; D006360:Heat-Shock Proteins; D010454:Peptide Termination Factors; D010797:Phthalimides; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; C070972:HsP104 protein, S cerevisiae; D002392:Catechin; C045651:epigallocatechin gallate