TY - JOUR
T1 - Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid-core-containing hexapeptide
AU - Tatarek-Nossol, Marianna
AU - Yan, Li Mei
AU - Schmauder, Anke
AU - Tenidis, Konstantinos
AU - Westermark, Gunilla
AU - Kapurniotu, Aphrodite
N1 - Funding Information:
We are grateful to J. Bernhagen for help with the apoptosis assay and to A. Velkova for help with the fluorescence spectroscopy. We thank K. Sweimeh for technical assistance in CD and EM studies. We thank M. Waldner, H. Vasan, and M. Müsken for technical assistance in peptide synthesis, purification, and fluorescein labeling. This work was partially supported by an institutional grant of The Fraunhofer Institute for Interfacial and Biological Engineering (FhIGB, Stuttgart, Germany).
PY - 2005/7
Y1 - 2005/7
N2 - The pathogenesis of type II diabetes is associated with the aggregation of the 37-residue human islet amyloid polypeptide (hIAPP) into cytotoxic β sheet aggregates and fibrils. We have recently shown that introduction of two N-methyl rests in the β 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 β 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.
AB - The pathogenesis of type II diabetes is associated with the aggregation of the 37-residue human islet amyloid polypeptide (hIAPP) into cytotoxic β sheet aggregates and fibrils. We have recently shown that introduction of two N-methyl rests in the β 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 β 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.
UR - http://www.scopus.com/inward/record.url?scp=22544474421&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2005.05.010
DO - 10.1016/j.chembiol.2005.05.010
M3 - Article
C2 - 16039527
AN - SCOPUS:22544474421
SN - 1074-5521
VL - 12
SP - 797
EP - 809
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 7
ER -
