Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N Terminus Hot Segments and Attenuates Cytotoxicity

Debabrata Maity, Yujeong Oh, Lothar Gremer, Wolfgang Hoyer, Mazin Magzoub, Andrew Hamilton

Research output: Contribution to journalArticlepeer-review

Abstract

Two “hot segments” within an islet amyloid polypeptide are responsible for its self-assembly, which in turn is linked to the decline of β-cells in type 2 diabetes (T2D). A readily available water-soluble, macrocyclic host, cucurbit[7]uril (CB[7]), effectively inhibits islet amyloid polypeptide (IAPP) aggregation through ion–dipole and hydrophobic interactions with different residues of the monomeric peptide in its random-coil conformation. A HSQC NMR study shows that CB[7] likely modulates IAPP self-assembly by interacting with and masking major residues present in the “hot segments” at the N terminus. CB[7] also prevents the formation of toxic oligomers and inhibits seed-catalyzed fibril proliferation. Importantly, CB[7] recovers rat insulinoma cells (RIN-m) from IAPP-assembly associated cytotoxicity.

Original languageEnglish (US)
JournalChemistry - A European Journal
DOIs
StateAccepted/In press - 2022

Keywords

  • amyloid fibrils
  • cucurbit[7]uril
  • islet amyloid polypeptides
  • macrocyclic hosts
  • protein assembly
  • type 2 diabetes

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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