File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Design of peptide-based inhibitors of human islet amyloid polypeptide fibrillogenesis

TitleDesign of peptide-based inhibitors of human islet amyloid polypeptide fibrillogenesis
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2002
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
Citation
Journal of Molecular Biology, 2002, v. 318 n. 3, p. 697-706 How to Cite?
AbstractHuman islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in the pancreas of over 90% of all cases of type-2 diabetes. We have generated a series of overlapping hexapeptides to target an amyloidogenic region of IAPP (residues 20-29) and examined their effects on fibril assembly. Peptide fragments corresponding to SNNFGA (residues 20-25) and GAILSST (residues 24-29) were strong inhibitors of the β-sheet transition and amyloid aggregation. Circular dichroism indicated that even at 1:1 molar ratios, these peptides maintained full-length IAPP (1-37) in a largely random coil conformation. Negative stain electron microscopy revealed that co-incubation of these peptides with IAPP resulted in the formation of only semi-fibrous aggregates and loss of the typical high density and morphology of IAPP fibrils. This inhibitory activity, particularly for the SNNFGA sequence, also correlated with a reduction in IAPP-induced cytotoxicity as determined by cell culture studies. In contrast, the peptide NFGAIL (residues 22-27) enhanced IAPP fibril formation. Conversion to the amyloidogenic β-sheet was immediate and the accompanying fibrils were more dense and complex than IAPP alone. The remaining peptide fragments either had no detectable effects or were only weakly inhibitory. Specificity of peptide activity was illustrated by the fragments, SSNNFG and AILSST. These differed from the most active inhibitors by only a single amino acid residue but delayed the random-to-β conformational change only when used at higher molar ratios. This study has identified internal IAPP peptide fragments which can regulate fibrillogenesis and may be of therapeutic use for the treatment of type-2 diabetes. © 2002 Elsevier Science Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/92174
ISSN
2015 Impact Factor: 4.517
2015 SCImago Journal Rankings: 3.002
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorScrocchi, LAen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorWaschuk, Sen_HK
dc.contributor.authorWang, Fen_HK
dc.contributor.authorCheung, Sen_HK
dc.contributor.authorDarabie, AAen_HK
dc.contributor.authorMcLaurin, Jen_HK
dc.contributor.authorFraser, PEen_HK
dc.date.accessioned2010-09-17T10:38:15Z-
dc.date.available2010-09-17T10:38:15Z-
dc.date.issued2002en_HK
dc.identifier.citationJournal of Molecular Biology, 2002, v. 318 n. 3, p. 697-706en_HK
dc.identifier.issn0022-2836en_HK
dc.identifier.urihttp://hdl.handle.net/10722/92174-
dc.description.abstractHuman islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in the pancreas of over 90% of all cases of type-2 diabetes. We have generated a series of overlapping hexapeptides to target an amyloidogenic region of IAPP (residues 20-29) and examined their effects on fibril assembly. Peptide fragments corresponding to SNNFGA (residues 20-25) and GAILSST (residues 24-29) were strong inhibitors of the β-sheet transition and amyloid aggregation. Circular dichroism indicated that even at 1:1 molar ratios, these peptides maintained full-length IAPP (1-37) in a largely random coil conformation. Negative stain electron microscopy revealed that co-incubation of these peptides with IAPP resulted in the formation of only semi-fibrous aggregates and loss of the typical high density and morphology of IAPP fibrils. This inhibitory activity, particularly for the SNNFGA sequence, also correlated with a reduction in IAPP-induced cytotoxicity as determined by cell culture studies. In contrast, the peptide NFGAIL (residues 22-27) enhanced IAPP fibril formation. Conversion to the amyloidogenic β-sheet was immediate and the accompanying fibrils were more dense and complex than IAPP alone. The remaining peptide fragments either had no detectable effects or were only weakly inhibitory. Specificity of peptide activity was illustrated by the fragments, SSNNFG and AILSST. These differed from the most active inhibitors by only a single amino acid residue but delayed the random-to-β conformational change only when used at higher molar ratios. This study has identified internal IAPP peptide fragments which can regulate fibrillogenesis and may be of therapeutic use for the treatment of type-2 diabetes. © 2002 Elsevier Science Ltd. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmben_HK
dc.relation.ispartofJournal of Molecular Biologyen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.titleDesign of peptide-based inhibitors of human islet amyloid polypeptide fibrillogenesisen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, Y:ychenc@hkucc.hku.hken_HK
dc.identifier.authorityChen, Y=rp1318en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/S0022-2836(02)00164-Xen_HK
dc.identifier.pmid12054816-
dc.identifier.scopuseid_2-s2.0-0036305837en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0036305837&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume318en_HK
dc.identifier.issue3en_HK
dc.identifier.spage697en_HK
dc.identifier.epage706en_HK
dc.identifier.isiWOS:000175767700008-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats