title: Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs.
abstract: Mechanisms to safely eliminate amyloids and preamyloid oligomers associated with many devastating diseases are urgently needed. Biophysical principles dictate that small molecules are unlikely to perturb large intermolecular protein-protein interfaces, let alone extraordinarily stable amyloid interfaces. Yet 4,5-dianilinophthalimide (DAPH-1) reverses Abeta42 amyloidogenesis and neurotoxicity, which is associated with Alzheimer's disease. Here, we show that DAPH-1 and select derivatives are ineffective against several amyloidogenic proteins, including tau, alpha-synuclein, Ure2, and PrP, but antagonize the yeast prion protein, Sup35, in vitro and in vivo. This allowed us to exploit several powerful new tools created for studying the conformational transitions of Sup35 and decipher the mechanisms by which DAPH-1 and related compounds antagonize the prion state. During fibrillization, inhibitory DAPHs alter the folding of Sup35's amyloidogenic core, preventing amyloidogenic oligomerization and specific recognition events that nucleate prion assembly. Select DAPHs also are capable of attacking preformed amyloids. They remodel Sup35 prion-specific intermolecular interfaces to create morphologically altered aggregates with diminished infectivity and self-templating activity. Our studies provide mechanistic insights and reinvigorate hopes for small-molecule therapies that specifically disrupt intermolecular amyloid contacts.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Martin L
authors.initials: ML
authors.lastname: Duennwald
authors.forename: Blake E
authors.initials: BE
authors.lastname: Roberts
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Rozeboom
authors.forename: Yingxin L
authors.initials: YL
authors.lastname: Zhang
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Steele
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Krishnan
authors.forename: Linhui Julie
authors.initials: LJ
authors.lastname: Su
authors.forename: Drees
authors.initials: D
authors.lastname: Griffin
authors.forename: Samrat
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.forename: Peter
authors.initials: P
authors.lastname: Weigele
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Blanchard
authors.forename: Jonathan
authors.initials: J
authors.lastname: King
authors.forename: Ashok A
authors.initials: AA
authors.lastname: Deniz
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Buchwald
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Ingram
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001692:Biological Transport; D001703:Biophysics / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry*; D010454:Peptide Termination Factors; D010797:Phthalimides / Q000737:chemistry*; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010454:Peptide Termination Factors; D010797:Phthalimides; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C075222:amyloid beta-protein (1-42); D003545:Cysteine; C098874:4,5-dianilinophthalimide