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.

DOI: 10.1073/pnas.0801934105

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@article{Wang2008DirectAS, title={Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs.}, author={Huan Wang and Martin L Duennwald and Blake E Roberts and Leslie M Rozeboom and Yingxin L Zhang and Andrew D Steele and Rajaraman Krishnan and Linhui Julie Su and Drees Griffin and Samrat Mukhopadhyay and Edward J Hennessy and Peter Weigele and Barbara J Blanchard and Jonathan King and Ashok A Deniz and Stephen L Buchwald and Vernon M Ingram and Susan Lindquist and James Shorter}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2008}, volume={105 20}, pages={7159-64} }