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

Nature Chemical Biology volume 5, pages 936–946 (2009)Cite this article

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.

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Figure 1: Model of Sup35 prion assembly and chemical structure of EGCG.
Figure 2: EGCG inhibits assembly of select Sup35 prion strains.
Figure 3: EGCG prevents inter- and intramolecular contact formation of select Sup35 prion strains.
Figure 4: EGCG disrupts preformed inter- and intramolecular contacts of select Sup35 prion strains.
Figure 5: EGCG eliminates select Sup35 prion strains.
Figure 6: Combinations of DAPH-12 and EGCG prevent formation of multiple prion strains.
Figure 7: Combinations of DAPH-12 and EGCG remodel multiple prion strains.
Figure 8: EGCG and DAPH-12 synergize to cure various [PSI+] variants.

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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.).

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  1. Blake E Roberts and Martin L Duennwald: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Martin L Duennwald or James Shorter.

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Roberts, B., Duennwald, M., Wang, H. et al. A synergistic small-molecule combination directly eradicates diverse prion strain structures. Nat Chem Biol 5, 936–946 (2009). https://doi.org/10.1038/nchembio.246

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