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Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid-core-containing hexapeptide
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2005 (English)In: Chemistry and Biology, ISSN 1074-5521, Vol. 12, no 7, 797-809 p.Article in journal (Refereed) Published
Abstract [en]

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. ©2005 Elsevier Ltd All rights reserved.

Place, publisher, year, edition, pages
2005. Vol. 12, no 7, 797-809 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-30528DOI: 10.1016/j.chembiol.2005.05.010Local ID: 16110OAI: diva2:251350
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2011-01-12

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Westermark, Gunilla
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Faculty of Health SciencesDivision of cell biology
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