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A synergistic small-molecule combination directly eradicates diverse prion strain structures

Nature Chemical Biology volume 5, pages 936946 (2009) | Download Citation

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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.

  • Compound C22H18O11

    Epigallocatechin-3-gallate

  • Compound C22H19N3O4

    4,5-Bis-(4-methoxyanilino)phthalimide

  • Compound C15H14O7

    Epigallocatechin

  • Compound C7H6O5

    Gallic acid

  • Compound C8H6N2O2

    N-Aminophthalimide

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Acknowledgements

We thank E. Hennessy (Massachusetts Institute of Technology), S. Buchwald (Massachusetts Institute of Technology), R. Krishnan (Whitehead Institute for Biomedical Research), S. Lindquist (Whitehead Institute for Biomedical Research), J. Weissman (University of California San Francisco), R. Wetzel (University of Pittsburgh School of Medicine) and C. Glabe (University of California Irvine) for generous provision of reagents; J. Chan for preliminary in vivo experiments; and M. Lemmon, A. Gitler, S.B. Cullinan, N. Bonini and S.W. Englander for comments on the manuscript. This work was supported by US National Institutes of Health (NIH) training grant 2T32GM008275-21 (E.A.S), an NIH Director's New Innovator Award (DP2OD002177), an Ellison Medical Foundation New Scholar in Aging Award, an American Heart Association Scientist Development Grant, and University of Pennsylvania Institute on Aging and Alzheimer's Disease Core Center pilots (J.S.).

Author information

Author notes

    • Blake E Roberts
    •  & Martin L Duennwald

    These authors contributed equally to this work.

Affiliations

  1. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Blake E Roberts
    • , Huan Wang
    • , Nicholas P Lopreiato
    • , Elizabeth A Sweeny
    • , M Noelle Knight
    •  & James Shorter
  2. Boston Biomedical Research Institute, Watertown, Massachusetts, USA.

    • Martin L Duennwald
    •  & Chan Chung

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Contributions

B.E.R., M.L.D., H.W., C.C., N.P.L., E.A.S. and J.S. designed experiments, contributed key reagents, performed experiments and interpreted data. M.N.K. contributed key reagents. M.L.D. and J.S. wrote the manuscript.

Corresponding authors

Correspondence to Martin L Duennwald or James Shorter.

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DOI

https://doi.org/10.1038/nchembio.246

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