{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:24:25Z","timestamp":1790148265464,"version":"4.0.1"},"reference-count":44,"publisher":"American Chemical Society (ACS)","issue":"3","license":[{"start":{"date-parts":[[2015,12,22]],"date-time":"2015-12-22T00:00:00Z","timestamp":1450742400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM078114"],"award-info":[{"award-number":["GM078114"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000138","name":"U.S. Department of Education","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000138","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/I015361\/1"],"award-info":[{"award-number":["BB\/I015361\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["322408"],"award-info":[{"award-number":["322408"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Waters Corporation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to \u03b2-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer\u2019s disease A\u03b2 peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP. In this study, we use a series of IAPP variants to examine possible interactions between resveratrol and IAPP. Fluorescence assays, transmission electron microscopy, and mass spectrometry demonstrate that resveratrol is much less effective as an inhibitor of IAPP amyloid formation than the polyphenol (\u2212)-epigallocatechin 3-gallate (EGCG) and, unlike EGCG, does not significantly disaggregate preformed IAPP amyloid fibrils. Resveratrol is also shown to interfere with thioflavin-T assays. His-18 mutants, a truncation mutant, mutants of each of the aromatic residues, and mutants of Arg-11 of IAPP were examined. Mutation of His to Gln or Leu weakens the ability of resveratrol to inhibit amyloid formation by IAPP, as do mutations of Arg-11, Phe-15, or Tyr-37 to Leu, and truncation to form the variant Ac 8\u221237-IAPP, which removes the first seven residues to eliminate Lys-1 and the N-terminal amino group. In contrast, replacement of Phe-23 with Leu has a smaller effect. The data highlight Phe-15, His-18, and Tyr-37 as being important for IAPP\u2013resveratrol interactions and are consistent with a potential role of the N-terminus and Arg-11 in polypeptide\u2013resveratrol interactions.<\/jats:p>","DOI":"10.1021\/bi501016r","type":"journal-article","created":{"date-parts":[[2014,12,22]],"date-time":"2014-12-22T13:51:47Z","timestamp":1419256307000},"page":"666-676","source":"Crossref","is-referenced-by-count":60,"title":["Mutational Analysis of the Ability of Resveratrol\nTo Inhibit Amyloid Formation by Islet Amyloid Polypeptide: Critical\nEvaluation of the Importance of Aromatic\u2013Inhibitor and Histidine\u2013Inhibitor\nInteractions"],"prefix":"10.1021","volume":"54","author":[{"given":"Ling-Hsien","family":"Tu","sequence":"first","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia M.","family":"Young","sequence":"additional","affiliation":[{"name":"University of Leeds , , Woodhouse Lane , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy G.","family":"Wong","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison E.","family":"Ashcroft","sequence":"additional","affiliation":[{"name":"University of Leeds , , Woodhouse Lane , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheena E.","family":"Radford","sequence":"additional","affiliation":[{"name":"University of Leeds , , Woodhouse Lane , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]},{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,12,22]]},"reference":[{"key":"2026090213172036100_cit1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2337\/diabetes.48.2.241","article-title":"Islet amyloid: A long-recognized\nbut underappreciated pathological feature of type 2 diabetes","volume":"48","author":"Kahn","year":"1999","journal-title":"Diabetes"},{"key":"2026090213172036100_cit2","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1210\/jc.2004-0405","article-title":"Islet amyloid: A\ncritical entity in the pathogenesis of type 2 diabetes","volume":"89","author":"Hull","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2026090213172036100_cit3","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1111\/j.1742-4658.2006.05367.x","article-title":"The\naggregation potential of human amylin determines its cytotoxicity\ntowards islet beta-cells","volume":"273","author":"Konarkowska","year":"2006","journal-title":"FEBS J."},{"key":"2026090213172036100_cit4","first-page":"A410","article-title":"Cytotoxic effects of\nhuman islet amyloid polypeptide\non primary islet \u03b1-cells and \u03b2-cells: Implications for\nunderstanding the pathogenesis of type 2 diabetes","volume":"56","author":"Cheng","year":"2007","journal-title":"Diabetes"},{"key":"2026090213172036100_cit5","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1210\/er.2007-0037","article-title":"Islet amyloid in\ntype 2 diabetes, and the toxic oligomer hypothesis","volume":"29","author":"Haataja","year":"2008","journal-title":"Endocrinol. Rev."},{"key":"2026090213172036100_cit6","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1152\/physrev.00042.2009","article-title":"Islet amyloid polypeptide, islet\namyloid, and diabetes mellitus","volume":"91","author":"Westermark","year":"2011","journal-title":"Physiol. Rev."},{"key":"2026090213172036100_cit7","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3109\/2000-1967-113","article-title":"Formation\nof amyloid in human pancreatic islets transplanted\nto the liver and spleen of nude mice","volume":"108","author":"Westermark","year":"2003","journal-title":"Upsala\nJ. Med. Sci."},{"key":"2026090213172036100_cit8","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1056\/NEJMc0802893","article-title":"Widespread amyloid deposition in transplanted human\npancreatic islets","volume":"359","author":"Westermark","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2026090213172036100_cit9","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1073\/pnas.0909024107","article-title":"Islet amyloid deposition\nlimits the viability of human islet grafts but not porcine islet grafts","volume":"107","author":"Potter","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090213172036100_cit10","doi-asserted-by":"crossref","first-page":"634","DOI":"10.2337\/diab.39.5.634","article-title":"Evidence of cosecretion of islet\namyloid polypeptide and insulin by \u03b2-cells","volume":"39","author":"Kahn","year":"1990","journal-title":"Diabetes"},{"key":"2026090213172036100_cit11","first-page":"E457","article-title":"Effects\nof amylin on glucose-metabolism and glycogenolysis in vivo and in\nvitro","volume":"259","author":"Young","year":"1990","journal-title":"Am. J. Physiol."},{"key":"2026090213172036100_cit12","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.brainres.2008.02.107","article-title":"Green tea\nepigallocatechin-3-gallate (EGCG) reduces \u03b2-amyloid mediated\ncognitive impairment and modulates tau pathology in Alzheimer transgenic\nmice","volume":"1214","author":"Rezai-Zadeh","year":"2008","journal-title":"Brain Res."},{"key":"2026090213172036100_cit13","doi-asserted-by":"crossref","first-page":"8127","DOI":"10.1021\/bi100939a","article-title":"The flavanol\n(\u2212)-epigallocatechin 3-gallate inhibits amyloid formation by\nislet amyloid polypeptide, disaggregates amyloid fibrils, and protects\ncultured cells against IAPP-induced toxicity","volume":"49","author":"Meng","year":"2010","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit14","doi-asserted-by":"crossref","first-page":"7710","DOI":"10.1073\/pnas.0910723107","article-title":"EGCG remodels mature\n\u03b1-synuclein and amyloid-\u03b2 fibrils and reduces cellular\ntoxicity","volume":"107","author":"Bieschke","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090213172036100_cit15","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1021\/jp2121577","article-title":"Site specific interaction of the polyphenol EGCG with\nthe SEVI amyloid precursor peptide PAP(248\u2013286)","volume":"116","author":"Popovych","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"2026090213172036100_cit16","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1021\/bi2015162","article-title":"Analysis\nof the inhibition and remodeling of islet\namyloid polypeptide amyloid fibers by flavanols","volume":"51","author":"Cao","year":"2012","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit17","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1021\/ja406831n","article-title":"Ion mobility spectrometry-mass\nspectrometry defines the oligomeric intermediates in amylin amyloid\nformation and the mode of action of inhibitors","volume":"136","author":"Young","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2026090213172036100_cit18","doi-asserted-by":"crossref","first-page":"7503","DOI":"10.1021\/ja3115696","article-title":"Toward the molecular mechanism(s)\nby which EGCG treatment remodels mature amyloid fibrils","volume":"135","author":"Palhano","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"2026090213172036100_cit19","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nsmb.1437","article-title":"EGCG redirects\namyloidogenic polypeptides into unstructured, off-pathway oligomers","volume":"15","author":"Ehrnhoefer","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026090213172036100_cit20","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12035-010-8111-y","article-title":"Resveratrol as a\ntherapeutic agent for neurodegenerative diseases","volume":"41","author":"Sun","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"2026090213172036100_cit21","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1159\/000073766","article-title":"Red wine ingredient resveratrol protects from \u03b2-amyloid\nneurotoxicity","volume":"49","author":"Savaskan","year":"2003","journal-title":"Gerontology"},{"key":"2026090213172036100_cit22","doi-asserted-by":"crossref","first-page":"37377","DOI":"10.1074\/jbc.M508246200","article-title":"Resveratrol promotes\nclearance of\nAlzheimer\u2019s disease amyloid-\u03b2 peptides","volume":"280","author":"Marambaud","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026090213172036100_cit23","doi-asserted-by":"crossref","first-page":"24228","DOI":"10.1074\/jbc.M110.133108","article-title":"Resveratrol selectively\nremodels soluble oligomers and fibrils of amyloid A-\u03b2 into off-pathway\nconformers","volume":"285","author":"Ladiwala","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090213172036100_cit24","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/cbic.200800762","article-title":"Inhibiting\nislet amyloid polypeptide fibril formation by the red wine compound\nresveratrol","volume":"10","author":"Mishra","year":"2009","journal-title":"ChemBioChem"},{"key":"2026090213172036100_cit25","doi-asserted-by":"crossref","first-page":"9516","DOI":"10.1021\/ja8097417","article-title":"Elucidating\nthe mechanism of lipid membrane-induced IAPP fibrillogenesis and its\ninhibition by the red wine compound resveratrol: A synchrotron X-ray\nreflectivity study","volume":"131","author":"Evers","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2026090213172036100_cit26","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.febslet.2009.03.059","article-title":"Fluorescence\nmicroscopy studies on\nislet amyloid polypeptide fibrillation at heterogeneous and cellular\nmembrane interfaces and its inhibition by resveratrol","volume":"583","author":"Radovan","year":"2009","journal-title":"FEBS Lett."},{"key":"2026090213172036100_cit27","doi-asserted-by":"crossref","first-page":"6291","DOI":"10.1074\/jbc.M110.166678","article-title":"The molecular basis of distinct aggregation\npathways of islet amyloid polypeptide","volume":"286","author":"Wei","year":"2011","journal-title":"J. Biol.\nChem."},{"key":"2026090213172036100_cit28","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/j.bpj.2013.12.052","article-title":"Mutational analysis\nof preamyloid intermediates: The role of His-Tyr interactions in islet\namyloid formation","volume":"106","author":"Tu","year":"2014","journal-title":"Biophys. J."},{"key":"2026090213172036100_cit29","doi-asserted-by":"crossref","first-page":"14454","DOI":"10.1021\/bi048582a","article-title":"Inhibition of islet\namyloid polypeptide fibril formation: A potential role for heteroaromatic\ninteractions","volume":"43","author":"Porat","year":"2004","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit30","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1021\/ol047480+","article-title":"Incorporation of pseudoproline derivatives\nallows the\nfacile synthesis of human IAPP, a highly amyloidogenic and aggregation-prone\npolypeptide","volume":"7","author":"Abedini","year":"2005","journal-title":"Org. Lett."},{"key":"2026090213172036100_cit31","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.1021\/ol101981b","article-title":"Efficient\nmicrowave-assisted synthesis of human islet amyloid polypeptide designed\nto facilitate the specific incorporation of labeled amino acids","volume":"12","author":"Marek","year":"2010","journal-title":"Org. Lett."},{"key":"2026090213172036100_cit32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ab.2005.11.029","article-title":"Recovery and purification of highly\naggregation-prone disulfide-containing peptides: Application to islet\namyloid polypeptide","volume":"351","author":"Abedini","year":"2006","journal-title":"Anal. Biochem."},{"key":"2026090213172036100_cit33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1747-0285.2005.00318.x","article-title":"Inhibition of amyloid fibril formation\nby polyphenols: Structural similarity and aromatic interactions as\na common inhibition mechanism","volume":"67","author":"Porat","year":"2006","journal-title":"Chem. Biol. Drug\nDes."},{"key":"2026090213172036100_cit34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jsb.2004.08.002","article-title":"The binding of thioflavin-T\nto amyloid fibrils: Localisation and implications","volume":"149","author":"Krebs","year":"2005","journal-title":"J. Struct. Biol."},{"key":"2026090213172036100_cit35","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.jmb.2010.05.041","article-title":"Residue-specific,\nreal-time characterization of lag-phase species and fibril growth\nduring amyloid formation: A combined fluorescence and IR study of p-cyanophenylalanine analogs of islet amyloid polypeptide","volume":"400","author":"Marek","year":"2010","journal-title":"J. Mol. Biol."},{"key":"2026090213172036100_cit36","doi-asserted-by":"crossref","first-page":"5960","DOI":"10.1111\/j.1742-4658.2009.07307.x","article-title":"The thioflavin T\nfluorescence assay for amyloid fibril detection can be biased by the\npresence of exogenous compounds","volume":"276","author":"Hudson","year":"2009","journal-title":"FEBS J."},{"key":"2026090213172036100_cit37","doi-asserted-by":"crossref","first-page":"6016","DOI":"10.1021\/bi702518m","article-title":"Rifampicin\ndoes not prevent amyloid fibril formation by human islet amyloid polypeptide\nbut does inhibit fibril thioflavin-T interactions: Implications for\nmechanistic studies \u03b2-cell death","volume":"47","author":"Meng","year":"2008","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit38","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1021\/bi0621967","article-title":"Aromatic\ninteractions are not required for amyloid fibril formation by islet\namyloid polypeptide but do influence the rate of fibril formation\nand fibril morphology","volume":"46","author":"Marek","year":"2007","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit39","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1021\/bi3014278","article-title":"Role of aromatic\ninteractions in amyloid formation\nby islet amyloid polypeptide","volume":"52","author":"Tu","year":"2013","journal-title":"Biochemistry"},{"key":"2026090213172036100_cit40","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/pro.2023","article-title":"Morin hydrate\ninhibits amyloid formation by islet amyloid\npolypeptide and disaggregates amyloid fibers","volume":"21","author":"Noor","year":"2012","journal-title":"Protein Sci."},{"issue":"5","key":"2026090213172036100_cit41","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1021\/jf9504576","article-title":"Resveratrol:\nIsomeric molar absorptivities and stability","volume":"44","author":"Trela","year":"1996","journal-title":"J. Agric. Food Chem."},{"issue":"8","key":"2026090213172036100_cit42","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1021\/bi101985j","article-title":"Structure of trans-Resveratrol\nin\nComplex with the Cardiac Regulatory Protein Troponin C","volume":"50","author":"Pineda-Sanabria","year":"2011","journal-title":"Biochemistry"},{"issue":"47","key":"2026090213172036100_cit43","doi-asserted-by":"crossref","first-page":"13505","DOI":"10.1021\/bi701427q","article-title":"Peptide conformation\nand supramolecular organization in amylin fibrils: Constraints from\nsolid-state NMR","volume":"46","author":"Luca","year":"2007","journal-title":"Biochemistry"},{"issue":"9","key":"2026090213172036100_cit44","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1110\/ps.036509.108","article-title":"Atomic structure of the cross-\u03b2 spine of islet\namyloid polypeptide (amylin)","volume":"17","author":"Wiltzius","year":"2008","journal-title":"Protein Sci."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi501016r","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/3\/666\/7876982\/bi501016r.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/54\/3\/666\/7876982\/bi501016r.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:17:34Z","timestamp":1788369454000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/54\/3\/666\/773145\/Mutational-Analysis-of-the-Ability-of-Resveratrol"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,22]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,12,22]]},"published-print":{"date-parts":[[2015,1,27]]}},"URL":"https:\/\/doi.org\/10.1021\/bi501016r","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,22]]}}}