Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid- core-containing hexapeptide.
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.
Tatarek-Nossol
Marianna
M
Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch-Westfälische Technische Hochschule Aachen, D-52074 Aachen, Germany.
Yan
Li-Mei
LM
Schmauder
Anke
A
Tenidis
Konstantinos
K
Westermark
Gunilla
G
Kapurniotu
Aphrodite
A
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000686:Amyloidosis / Q000175:diagnosis / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008745:Methylation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence
D000682:Amyloid; D009842:Oligopeptides; D010446:Peptide Fragments; C079438:islet amyloid polypeptide (8-37)