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

Aleksandr Kakinen, Jozef Adamcik, Bo Wang, Xinwei Ge, Raffaele Mezzenga, Thomas P. Davis, Feng Ding, Pu Chun Ke

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)3636-3647
Number of pages12
JournalNano Research
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2018

Keywords

  • discrete molecular
  • dynamics (DMD)
  • inhibition
  • islet amyloid polypeptides (IAPP) fibrillization
  • persistence length
  • simulations
  • small molecule

Cite this

Kakinen, Aleksandr ; Adamcik, Jozef ; Wang, Bo ; Ge, Xinwei ; Mezzenga, Raffaele ; Davis, Thomas P. ; Ding, Feng ; Ke, Pu Chun. / Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules. In: Nano Research. 2018 ; Vol. 11, No. 7. pp. 3636-3647.
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Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules. / Kakinen, Aleksandr; Adamcik, Jozef; Wang, Bo; Ge, Xinwei; Mezzenga, Raffaele; Davis, Thomas P.; Ding, Feng; Ke, Pu Chun.

In: Nano Research, Vol. 11, No. 7, 07.2018, p. 3636-3647.

Research output: Contribution to journalArticleResearchpeer-review

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