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Heteromultivalent peptide recognition by co-assembly of cyclodextrin and calixarene amphiphiles enables inhibition of amyloid fibrillation

Nature Chemistry volume 11, pages 86–93 (2019)Cite this article

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Abstract

Heteromultivalency, which involves the simultaneous interactions of more than one type of ligand with more than one type of receptor, is ubiquitous in living systems and provides a powerful strategy to improve the binding efficiency of heterotopic species such as proteins and membranes. However, the design and development of artificial heteromultivalent receptors is still challenging owing to tedious synthesis processes and the need for precise control over the spatial arrangement of the binding sites. Here, we have designed a heteromultivalent platform by co-assembling cyclodextrin and calixarene amphiphiles, so that two orthogonal, non-covalent binding sites are distributed on the surface of the co-assembly. Binding with model peptides shows a synergistic effect of the two receptors, (hetero)multivalency and self-adaptability. The co-assembly shows promise for inhibition of the fibrillation of amyloid-β peptides and the dissolution of amyloid-β fibrils, substantially reducing amyloid cytotoxicity. This self-assembled heteromultivalency concept is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged.

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Fig. 1: Illustration of the heteromultivalent peptide recognition by co-assembly of CD and CA amphiphiles.
Fig. 2: Structures of model peptides Aβ42 and DA-39.
Fig. 3: Fluorescence titration curves.
Fig. 4: CD−CA co-assembly inhibits Aβ42 aggregation and disaggregates Aβ42 fibrils.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information, and from the corresponding author upon reasonable request.

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Acknowledgements

The Chinese team acknowledges support from the NNSFC (21672112 and 51873090), Fundamental Research Funds for the Central Universities and the Program of Tianjin Young Talents. The German team thanks T. Böckerman for the synthesis of amphiphilic CD and the Deutsche Forschungsgemeinschaft (DFG SFB 858) for financial support.

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Authors and Affiliations

  1. College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials, Ministry of Education, Nankai University, Tianjin, China

    Zhe Xu, Wei Wang, Zhi Yuan & Dong-Sheng Guo

  2. Organic Chemistry Institute and Center for Soft Nanoscience (SoN), Westfälische Wilhelms-Universität Münster, Münster, Germany

    Zhe Xu & Bart Jan Ravoo

  3. College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, China

    Shaorui Jia

  4. Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, China

    Dong-Sheng Guo

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  1. Zhe Xu
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  2. Shaorui Jia
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  3. Wei Wang
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  4. Zhi Yuan
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Contributions

Z.X., B.J.R. and D.S.G. conceived the experiments. Z.X. prepared the assemblies and performed the heteromultivalent peptide recognition. Z.X., W.W. and Z.Y. performed the inhibition of amyloid fibrillation. S.J. performed the cell experiments. Z.X., B.J.R. and D.S.G. contributed to writing of the manuscript, and all authors commented on it.

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Correspondence to Bart Jan Ravoo or Dong-Sheng Guo.

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Supplementary materials and methods, Supplementary characterization, Supplementary Figs 1–27 and Supplementary References 1–9

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Xu, Z., Jia, S., Wang, W. et al. Heteromultivalent peptide recognition by co-assembly of cyclodextrin and calixarene amphiphiles enables inhibition of amyloid fibrillation. Nature Chem 11, 86–93 (2019). https://doi.org/10.1038/s41557-018-0164-y

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