DOI: 10.1073/pnas.0801934105. Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs [Penn]

Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs

10.1073/pnas.0801934105

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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 Aβ42 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, α-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.

Bibliography

Wang, H., Duennwald, M. L., Roberts, B. E., Rozeboom, L. M., Zhang, Y. L., Steele, A. D., Krishnan, R., Su, L. J., Griffin, D., Mukhopadhyay, S., Hennessy, E. J., Weigele, P., Blanchard, B. J., King, J., Deniz, A. A., Buchwald, S. L., Ingram, V. M., Lindquist, S., & Shorter, J. (2008). Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs. Proceedings of the National Academy of Sciences, 105(20), 7159â7164.

Authors 19

Huan Wang (first)
Martin L. Duennwald (additional)
Blake E. Roberts (additional)
Leslie M. Rozeboom (additional)
Yingxin L. Zhang (additional)
Andrew D. Steele (additional)
Rajaraman Krishnan (additional)
Linhui Julie Su (additional)
Drees Griffin (additional)
Samrat Mukhopadhyay (additional)
Edward J. Hennessy (additional)
Peter Weigele (additional)
Barbara J. Blanchard (additional)
Jonathan King (additional)
Ashok A. Deniz (additional)
Stephen L. Buchwald (additional)
Vernon M. Ingram (additional)
Susan Lindquist (additional)
James Shorter (additional)

References 30 Referenced 47

Dates

Type	When
Created	17 years, 3 months ago (May 14, 2008, 9:10 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 4:13 p.m.)
Indexed	1 month, 3 weeks ago (July 2, 2025, 2:33 p.m.)
Issued	17 years, 3 months ago (May 20, 2008)
Published	17 years, 3 months ago (May 20, 2008)
Published Online	17 years, 3 months ago (May 20, 2008)
Published Print	17 years, 3 months ago (May 20, 2008)

Funders 0

None

BibTeX

@article{Wang_2008, title={Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs}, volume={105}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0801934105}, DOI={10.1073/pnas.0801934105}, number={20}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Wang, Huan and Duennwald, Martin L. and Roberts, Blake E. and Rozeboom, Leslie M. and Zhang, Yingxin L. and Steele, Andrew D. and Krishnan, Rajaraman and Su, Linhui Julie and Griffin, Drees and Mukhopadhyay, Samrat and Hennessy, Edward J. and Weigele, Peter and Blanchard, Barbara J. and King, Jonathan and Deniz, Ashok A. and Buchwald, Stephen L. and Ingram, Vernon M. and Lindquist, Susan and Shorter, James}, year={2008}, month=may, pages={7159–7164} }

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  "abstract": "<jats:p>\n            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\u2013protein interfaces, let alone extraordinarily stable amyloid interfaces. Yet 4,5-dianilinophthalimide (DAPH-1) reverses A\u03b242 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, \u03b1-synuclein, Ure2, and PrP, but antagonize the yeast prion protein, Sup35,\n            <jats:italic>in vitro</jats:italic>\n            and\n            <jats:italic>in vivo</jats:italic>\n            . 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.\n          </jats:p>",
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