Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs
- 20 May 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (20), 7159-7164
- https://doi.org/10.1073/pnas.0801934105
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.Keywords
This publication has 30 references indexed in Scilit:
- Prion recognition elements govern nucleation, strain specificity and species barriersNature, 2007
- Atomic structures of amyloid cross-β spines reveal varied steric zippersNature, 2007
- A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structuresProceedings of the National Academy of Sciences of the United States of America, 2007
- Structural Models of Amyloid‐Like FibrilsAdvances in protein chemistry, 2006
- Green tea (−)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease modelsHuman Molecular Genetics, 2006
- Destruction or Potentiation of Different Prions Catalyzed by Similar Hsp104 Remodeling ActivitiesMolecular Cell, 2006
- Small Molecule Inhibitors of α-Synuclein Filament AssemblyBiochemistry, 2006
- NEURODEGENERATIVE DISEASES: New Concepts of Pathogenesis and Their Therapeutic ImplicationsAnnual Review Of Pathology-Mechanisms Of Disease, 2006
- 3D structure of Alzheimer's amyloid-β(1–42) fibrilsProceedings of the National Academy of Sciences of the United States of America, 2005
- Structural insights into a yeast prion illuminate nucleation and strain diversityNature, 2005