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Small-molecule aggregates inhibit amyloid polymerization

Abstract

Many amyloid inhibitors resemble molecules that form chemical aggregates, which are known to inhibit many proteins. Eight known chemical aggregators inhibited amyloid formation of the yeast and mouse prion proteins Sup35 and recMoPrP in a manner characteristic of colloidal inhibition. Similarly, three known anti-amyloid molecules inhibited β-lactamase in a detergent-dependent manner, which suggests that they too form colloidal aggregates. The colloids localized to preformed fibers and prevented new fiber formation in electron micrographs. They also blocked infection of yeast cells with Sup35 prions, which suggests that colloidal inhibition may be relevant in more biological milieus.

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Figure 1: Chemical aggregators inhibit amyloid formation in biochemical assays.
Figure 2: Chemical aggregators inhibit prion infection in yeast culture.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (GM71630 to B.K.S. and AG02132, AG10770 and AG021601 to S.B.P.) and by a gift from the G. Harold and Leila Y. Mathers Charitable Foundation (to S.B.P.). B.Y.F. is supported by a Kozloff research fellowship and by a University of California San Francisco School of Pharmacy fellowship. B.H.T. is supported by an Achievement Rewards for College Scientists foundation fellowship and by the Howard Hughes Medical Institute. D.W.C. is supported by a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. S.R.C. is supported by a predoctoral fellowship from the Burroughs Wellcome Fund and by the Howard Hughes Medical Institute. We thank V. Thomas, M. Diamond and B. Frost for thoughtful discussion and K. Coan for reading this manuscript.

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Contributions

B.Y.F. performed the experiments unless otherwise noted, and wrote the manuscript with B.K.S. B.H.T. helped perform the Sup35 infectivity assay. H.W. performed the electron microscopy studies. D.W.C. performed the recMoPrP polymerization experiments. S.R.C. helped perform the Sup35 polymerization experiments. B.C.H.M., S.B.P. and J.W. provided guidance and helped edit the manuscript.

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Correspondence to Brian K Shoichet.

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B.C.H.M. and S.B.P. declare a financial interest in Inpro Biotechnology, Inc. All other authors declare no competing interests.

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Supplementary Figures 1–4, Supplementary Tables 1–3 and Supplementary Methods (PDF 2658 kb)

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Feng, B., Toyama, B., Wille, H. et al. Small-molecule aggregates inhibit amyloid polymerization. Nat Chem Biol 4, 197–199 (2008). https://doi.org/10.1038/nchembio.65

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