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Article: Inhibitors of islet amyloid polypeptide fibrillogenesis, and the treatment of type-2 diabetes

TitleInhibitors of islet amyloid polypeptide fibrillogenesis, and the treatment of type-2 diabetes
Authors
KeywordsΒ Cells
Amyloid Fibrils
Apoptosis
Circular Dichroism
Diabetes
Electron Microscopy
Islet Amyloid Polypeptide
Issue Date2003
Citation
Letters in Peptide Science, 2003, v. 10 n. 5-6, p. 545-551 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. Although it may be a secondary event in the etiology of diabetes, the accumulation of insoluble IAPP fibrils is considered to be a primary cause of β-cell failure in affected individuals. A possible means of inhibiting this process is through the use of small peptides that bind to IAPP and prevent fibril polymerization. This approach has been examined using a series of overlapping hexamers that target the known amyloidogenic regions of IAPP. Peptides were examined usingin vitroassays and active inhibitors were identified by their ability to prevent amyloid-related conformational transitions and IAPP aggregation. Fragments such as those corresponding to the IAPP-derived sequences, SNNFGA (residues 20-25) and GAILSS (residues 24-29), were potent inhibitors of β-sheet folding and amyloid fibril formation. Negative stain electron microscopy revealed that co-incubation of these peptides with IAPP significantly decreased the density of fibrils and any remaining structures displayed altered morphology. In some, but not all cases, inhibition of amyloid fibrils also correlated with an ability to reduce IAPP-mediated cytotoxicity as determined in cell culture studies. The results from these studies suggest that these two peptide inhibitors differ in their mechanisms of action possibly due to unique interactions with the full-length IAPP molecule. These inhibitors form the basis of a therapeutic strategy to prevent amyloid accumulation leading to improved islet survival and a potentially novel treatment for type-2 diabetes. © 2004 Kluwer Academic Publishers.
Persistent Identifierhttp://hdl.handle.net/10722/92287
ISSN
2005 Impact Factor: 0.406
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorScrocchi, LAen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorWang, Fen_HK
dc.contributor.authorHan, Ken_HK
dc.contributor.authorHa, Ken_HK
dc.contributor.authorWu, Len_HK
dc.contributor.authorFraser, PEen_HK
dc.date.accessioned2010-09-17T10:41:35Z-
dc.date.available2010-09-17T10:41:35Z-
dc.date.issued2003en_HK
dc.identifier.citationLetters in Peptide Science, 2003, v. 10 n. 5-6, p. 545-551en_HK
dc.identifier.issn0929-5666en_HK
dc.identifier.urihttp://hdl.handle.net/10722/92287-
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. Although it may be a secondary event in the etiology of diabetes, the accumulation of insoluble IAPP fibrils is considered to be a primary cause of β-cell failure in affected individuals. A possible means of inhibiting this process is through the use of small peptides that bind to IAPP and prevent fibril polymerization. This approach has been examined using a series of overlapping hexamers that target the known amyloidogenic regions of IAPP. Peptides were examined usingin vitroassays and active inhibitors were identified by their ability to prevent amyloid-related conformational transitions and IAPP aggregation. Fragments such as those corresponding to the IAPP-derived sequences, SNNFGA (residues 20-25) and GAILSS (residues 24-29), were potent inhibitors of β-sheet folding and amyloid fibril formation. Negative stain electron microscopy revealed that co-incubation of these peptides with IAPP significantly decreased the density of fibrils and any remaining structures displayed altered morphology. In some, but not all cases, inhibition of amyloid fibrils also correlated with an ability to reduce IAPP-mediated cytotoxicity as determined in cell culture studies. The results from these studies suggest that these two peptide inhibitors differ in their mechanisms of action possibly due to unique interactions with the full-length IAPP molecule. These inhibitors form the basis of a therapeutic strategy to prevent amyloid accumulation leading to improved islet survival and a potentially novel treatment for type-2 diabetes. © 2004 Kluwer Academic Publishers.en_HK
dc.languageengen_HK
dc.relation.ispartofLetters in Peptide Scienceen_HK
dc.subjectΒ Cellsen_HK
dc.subjectAmyloid Fibrilsen_HK
dc.subjectApoptosisen_HK
dc.subjectCircular Dichroismen_HK
dc.subjectDiabetesen_HK
dc.subjectElectron Microscopyen_HK
dc.subjectIslet Amyloid Polypeptideen_HK
dc.titleInhibitors of islet amyloid polypeptide fibrillogenesis, and the treatment of type-2 diabetesen_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.doi10.1007/BF02442587en_HK
dc.identifier.scopuseid_2-s2.0-15044344416en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-15044344416&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume10en_HK
dc.identifier.issue5-6en_HK
dc.identifier.spage545en_HK
dc.identifier.epage551en_HK
dc.identifier.isiWOS:000226731400022-

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