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Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

Nature Chemistry volume 4, pages 927–933 (2012)Cite this article

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Abstract

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

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Figure 1: Design of ABSM 1.
Figure 2: X-ray crystallographic structure of ABSM 1r, which contains the heptapeptide sequence AIIGLMV (Aβ30–36).
Figure 3: Effect of ABSMs on inhibition of Aβ40, Aβ42, hβ2M and hαSyn1–100 aggregation monitored by thioflavin T fluorescence assays and TEM.
Figure 4: Effect of ABSM 1a on Aβ40 and Aβ42 toxicity towards PC-12 cells.
Figure 5: β-Sheet interactions of Aβ peptides and ABSM 1a.

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Acknowledgements

The authors acknowledge support from the NIH (5R01 GM049076, 1R01 GM097562 and 1R01 AG029430), the NSF (CHE-1112188, CHE-0750523 and MCB-0445429) and HHMI. The authors also thank A. Berk and D. Gou for help with tissue culture experiments, and S. Blum for suggestions for Fig. 5a.

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Author notes

  1. Pin-Nan Cheng and Cong Liu: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, University of California, Irvine, 92697-2025, California, USA

    Pin-Nan Cheng & James S. Nowick

  2. UCLA-DOE Institute for Genomics and Proteomics, Howard Hughes Medical Institute, Molecular Biology Institute, University of California, Los Angeles, 90095-1570, California, USA

    Cong Liu, Minglei Zhao & David Eisenberg

Authors
  1. Pin-Nan Cheng
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  2. Cong Liu
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  4. David Eisenberg
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Contributions

P.-N.C., C.L., D.E. and J.S.N. designed the research. P.-N.C., C.L. and M.Z. performed the research. P.-N.C., C.L., M.Z., D.E. and J.S.N. analysed the data. P.-N.C., C.L., M.Z., D.E. and J.S.N. wrote the paper.

Corresponding authors

Correspondence to David Eisenberg or James S. Nowick.

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The authors declare no competing financial interests.

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Cheng, PN., Liu, C., Zhao, M. et al. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity. Nature Chem 4, 927–933 (2012). https://doi.org/10.1038/nchem.1433

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