Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid- core-containing hexapeptide

Chem Biol. 2005 Jul;12(7):797-809. doi: 10.1016/j.chembiol.2005.05.010.


The pathogenesis of type II diabetes is associated with the aggregation of the 37-residue human islet amyloid polypeptide (hIAPP) into cytotoxic beta sheet aggregates and fibrils. We have recently shown that introduction of two N-methyl rests in the beta sheet- and amyloid-core-containing sequence hIAPP(22-27), or NFGAIL converted this amyloidogenic and cytotoxic sequence into nonamyloidogenic and noncytotoxic NF(N-Me)GA(N-Me)IL. Here, we show that NF(N-Me)GA(N-Me)IL is able to bind with high-affinity full-length hIAPP and to inhibit its fibrillogenesis. NF(N-Me)GA(N-Me)IL also inhibits hIAPP-mediated apoptotic beta cell death. By contrast, unmodified NFGAIL does not inhibit hIAPP amyloidogenesis and cytotoxicity, suggesting that N-methylation conferred on NFGAIL the properties of NF(N-Me)GA(N-Me)IL. These results support the concept that rational N-methylation of hIAPP amyloid-core sequences may be a valuable strategy to design pancreatic-amyloid diagnostics and therapeutics for type II diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / antagonists & inhibitors*
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloid / pharmacology
  • Amyloidosis / diagnosis
  • Amyloidosis / drug therapy
  • Cell Death / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Methylation
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Spectrometry, Fluorescence


  • Amyloid
  • Oligopeptides
  • Peptide Fragments
  • islet amyloid polypeptide (8-37)