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Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules

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Abstract

Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human islet amyloid polypeptides (IAPP) in the fibrillar form are polymorphic, ambidextrous, and possess multiple periodicities. Upon interfacing with the small molecule epigallocatechin gallate (EGCG), IAPP aggregation was rendered off-pathway and assumed a form with soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial in delineating IAPP toxicity implicated in type 2 diabetes and for developing new inhibitors against amyloidogenesis.

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Acknowledgements

This work was supported by ARC Project No. CE140100036 (T. P. D.), NSF CAREER grant CBET- 1553945 (F. D.), NIH 1R35GM119691 (F. D.), and an internal grant from Monash Institute of Pharmaceutical Sciences (P. C. K.).

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Authors and Affiliations

  1. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Aleksandr Kakinen, Thomas P. Davis & Pu Chun Ke

  2. Food & Soft Materials, Department of Health Sciences & Technology, ETH Zurich, Schmelzbergstrasse 9, LFO, E23, 8092, Zurich, Switzerland

    Jozef Adamcik & Raffaele Mezzenga

  3. Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA

    Bo Wang, Xinwei Ge & Feng Ding

  4. Department of Chemistry, Warwick University, Gibbet Hill, Coventry, CV4 7AL, UK

    Thomas P. Davis

Authors
  1. Aleksandr Kakinen
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  2. Jozef Adamcik
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  3. Bo Wang
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  4. Xinwei Ge
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  5. Raffaele Mezzenga
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  6. Thomas P. Davis
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  7. Feng Ding
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Correspondence to Raffaele Mezzenga, Thomas P. Davis, Feng Ding or Pu Chun Ke.

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Kakinen, A., Adamcik, J., Wang, B. et al. Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules. Nano Res. 11, 3636–3647 (2018). https://doi.org/10.1007/s12274-017-1930-7

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  • DOI: https://doi.org/10.1007/s12274-017-1930-7

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