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Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly

Author

Listed:
  • Yong Xu

    (University of Leeds)

  • Roberto Maya-Martinez

    (University of Leeds)

  • Nicolas Guthertz

    (University of Leeds)

  • George R. Heath

    (University of Leeds)

  • Iain W. Manfield

    (University of Leeds)

  • Alexander L. Breeze

    (University of Leeds)

  • Frank Sobott

    (University of Leeds)

  • Richard Foster

    (University of Leeds)

  • Sheena E. Radford

    (University of Leeds)

Abstract

Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D.

Suggested Citation

  • Yong Xu & Roberto Maya-Martinez & Nicolas Guthertz & George R. Heath & Iain W. Manfield & Alexander L. Breeze & Frank Sobott & Richard Foster & Sheena E. Radford, 2022. "Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28660-7
    DOI: 10.1038/s41467-022-28660-7
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    References listed on IDEAS

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    1. Ryan Limbocker & Sean Chia & Francesco S. Ruggeri & Michele Perni & Roberta Cascella & Gabriella T. Heller & Georg Meisl & Benedetta Mannini & Johnny Habchi & Thomas C. T. Michaels & Pavan K. Challa &, 2019. "Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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    Cited by:

    1. Fabian Wirth & Fabrice D. Heitz & Christine Seeger & Ioana Combaluzier & Karin Breu & Heather C. Denroche & Julien Thevenet & Melania Osto & Paolo Arosio & Julie Kerr-Conte & C. Bruce Verchere & Franç, 2023. "A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. V. S. Manu & Cristina Olivieri & Gianluigi Veglia, 2023. "AI-designed NMR spectroscopy RF pulses for fast acquisition at high and ultra-high magnetic fields," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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