{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:16:48Z","timestamp":1788470208912,"version":"build-2803163510"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2015,8,20]],"date-time":"2015-08-20T00:00:00Z","timestamp":1440028800000},"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"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human islet amyloid polypeptide (hIAPP or amylin) is a polypeptide hormone produced in the pancreatic \u03b2-cells that plays a role in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes and is a promising adjunct to insulin therapy. However, hIAPP rapidly forms amyloid, and its strong tendency to aggregate limits its usefulness. The process of hIAPP amyloid formation is toxic to cultured \u03b2-cells and islets, and islet amyloid formation in vivo has been linked to \u03b2-cell death and islet graft failure. An analogue of hIAPP with a weakened tendency to aggregate, denoted pramlintide (PM), has been approved for clinical applications, but suffers from poor solubility, particularly at physiological pH, and its unfavorable solubility profile prevents coformulation with insulin. We describe a strategy for rationally designing analogues of hIAPP with improved properties; key proline mutations are combined with substitutions that increase the net charge of the molecule. An H18R\/G24P\/I26P triple mutant and an H18R\/A25P\/S28P\/S29P quadruple mutant are significantly more soluble at neutral pH than hIAPP or PM. They are nonamyloidogenic and are not toxic to rat INS \u03b2-cells. The approach is not limited to these examples; additional analogues can be designed using this strategy. To illustrate this point, we show that an S20R\/G24P\/I26P triple mutant and an H18R\/I26P double mutant are nonamyloidogenic and significantly more soluble than human IAPP or PM. These analogues and second-generation derivatives are potential candidates for the coformulation of IAPP with insulin and other polypeptides.<\/jats:p>","DOI":"10.1021\/bi500592p","type":"journal-article","created":{"date-parts":[[2014,8,20]],"date-time":"2014-08-20T14:51:20Z","timestamp":1408546280000},"page":"5876-5884","source":"Crossref","is-referenced-by-count":43,"title":["Rationally Designed, Nontoxic, Nonamyloidogenic Analogues\nof Human Islet Amyloid Polypeptide with Improved Solubility"],"prefix":"10.1021","volume":"53","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andisheh","family":"Abedini","sequence":"additional","affiliation":[{"name":"New York University School of Medicine , 522 First Avenue , , ,","place":["New York, New York, United States, 10016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bela","family":"Ruzsicska","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]},{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,8,20]]},"reference":[{"key":"2026090316254150400_cit1","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.2165\/00003495-200464130-00003","article-title":"Pramlintide for the treatment of insulin-requiring\ndiabetes mellitus: Rationale and review of clinical data","volume":"64","author":"Kruger","year":"2004","journal-title":"Drugs"},{"key":"2026090316254150400_cit2","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1073\/pnas.84.23.8628","article-title":"Purification and\ncharacterization of a peptide from\namyloid-rich pancreases of type 2 diabetic patients","volume":"84","author":"Cooper","year":"1987","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090316254150400_cit3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0140-6736(87)90825-7","article-title":"Islet amyloid formed from diabetes-associated\npeptide may be pathogenic in type-2 diabetes","volume":"2","author":"Clark","year":"1987","journal-title":"Lancet"},{"key":"2026090316254150400_cit4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0026-0495(97)90170-0","article-title":"Dose-response for glucagonostatic\neffect of amylin in rats","volume":"46","author":"Gedulin","year":"1997","journal-title":"Metabolism"},{"key":"2026090316254150400_cit5","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.1210\/endo.142.11.8593","article-title":"Inhibition\nof central amylin signaling\nincreases food intake and body adiposity in rats","volume":"142","author":"Rushing","year":"2001","journal-title":"Endocrinology"},{"key":"2026090316254150400_cit6","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/BF01925572","article-title":"Amylin given by central or peripheral\nroutes decreases gastric emptying and intestinal transit in the rat","volume":"52","author":"Clementi","year":"1996","journal-title":"Experientia"},{"key":"2026090316254150400_cit7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1055\/s-0029-1211958","article-title":"The role\nof amylin in the physiology of glycemic control","volume":"106","author":"Scherbaum","year":"1998","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"2026090316254150400_cit8","first-page":"414","article-title":"Islet amyloid\nin type 2 human diabetes\nmellitus and adult diabetic cats contains a novel putative polypeptide\nhormone","volume":"127","author":"Westermark","year":"1987","journal-title":"Am. J. Pathol."},{"key":"2026090316254150400_cit9","first-page":"151","article-title":"Islet amyloid, increased A-cells, reduced B-cells and\nexocrine fibrosis: Quantitative changes in the pancreas in type 2\ndiabetes","volume":"9","author":"Clark","year":"1988","journal-title":"Diabetes Res. Clin. Pract."},{"key":"2026090316254150400_cit10","first-page":"291","article-title":"Pancreatic-islet cells\nin insular amyloidosis in human diabetic and\nnon-diabetic adults","volume":"81","author":"Westermark","year":"1973","journal-title":"AActa Pathol., Microbiol.\nImmunol. Scand., Sect. A"},{"key":"2026090316254150400_cit11","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/BF01219652","article-title":"The influence of amyloid deposits on the islet volume\nin maturity onset diabetes mellitus","volume":"15","author":"Westermark","year":"1978","journal-title":"Diabetologia"},{"key":"2026090316254150400_cit12","doi-asserted-by":"crossref","first-page":"562985","DOI":"10.1155\/2008\/562985","article-title":"Amyloid deposition in transplanted\nhuman pancreatic islets: A conceivable cause of their long-term failure","volume":"2008","author":"Andersson","year":"2008","journal-title":"Exp. Diabetes Res."},{"key":"2026090316254150400_cit13","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":"2026090316254150400_cit14","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/0140-6736(92)90785-2","article-title":"Amylin concentrations and glucose control","volume":"339","author":"Koda","year":"1992","journal-title":"Lancet"},{"key":"2026090316254150400_cit15","first-page":"566","article-title":"Amylin response following Sustacal(R) ingestion is\ndiminished in type II diabetic patients treated with insulin","volume":"39","author":"Fineman","year":"1996","journal-title":"Diabetologia"},{"key":"2026090316254150400_cit16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1177\/014572179902500310","article-title":"Clinical\nimplications of amylin and\namylin deficiency","volume":"25","author":"Kruger","year":"1999","journal-title":"Diabetes Educ."},{"key":"2026090316254150400_cit17","doi-asserted-by":"crossref","first-page":"5036","DOI":"10.1073\/pnas.87.13.5036","article-title":"Islet amyloid polypeptide: Pinpointing\namino acid residues\nlinked to amyloid fibril formation","volume":"87","author":"Westermark","year":"1990","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026090316254150400_cit18","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":"2026090316254150400_cit19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.jmb.2005.10.052","article-title":"Destabilization\nof human IAPP amyloid fibrils by proline\nmutations outside of the putative amyloidogenic domain: Is there a\ncritical amyloidogenic domain in human IAPP?","volume":"355","author":"Abedini","year":"2006","journal-title":"J. Mol. Biol."},{"key":"2026090316254150400_cit20","doi-asserted-by":"crossref","first-page":"7783","DOI":"10.1021\/bi100337p","article-title":"Selection\nfor nonamyloidogenic mutants of islet amyloid\npolypeptide (IAPP) identifies an extended region for amyloidogenicity","volume":"49","author":"Fox","year":"2010","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit21","doi-asserted-by":"crossref","first-page":"16284","DOI":"10.1021\/bi051432v","article-title":"The role of His-18 in amyloid formation by human islet\namyloid polypeptide","volume":"44","author":"Abedini","year":"2005","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit22","doi-asserted-by":"crossref","first-page":"11300","DOI":"10.1021\/ja072157y","article-title":"A single-point\nmutation converts\nthe highly amyloidogenic human islet amyloid polypeptide into a potent\nfibrillization inhibitor","volume":"129","author":"Abedini","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"2026090316254150400_cit23","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1111\/cbdd.12172","article-title":"Pinpointing proline substitution\nto be responsible for the loss of amyloidogenesis in IAPP","volume":"82","author":"Chakraborty","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"2026090316254150400_cit24","doi-asserted-by":"crossref","first-page":"19285","DOI":"10.1073\/pnas.1314481110","article-title":"Mechanism\nof IAPP amyloid fibril formation involves an intermediate with a transient\n\u03b2-sheet","volume":"110","author":"Buchanan","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090316254150400_cit25","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1021\/bi901751b","article-title":"The ability of rodent\nislet amyloid polypeptide to inhibit amyloid formation by human islet\namyloid polypeptide has important implications for the mechanism of\namyloid formation and the design of inhibitors","volume":"49","author":"Cao","year":"2010","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit26","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.2174\/1381612013397357","article-title":"Amylin\nreplacement with pramlintide as an adjunct to insulin therapy in type\n1 and type 2 diabetes mellitus: A physiological approach toward improved\nmetabolic control","volume":"7","author":"Weyer","year":"2001","journal-title":"Curr. Pharm. Des."},{"key":"2026090316254150400_cit27","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1055\/s-2002-34790","article-title":"The human\namylin analog, pramlintide, reduces postprandial hyperglucagonemia\nin patients with type 2 diabetes mellitus","volume":"34","author":"Fineman","year":"2002","journal-title":"Horm.\nMetab. Res."},{"key":"2026090316254150400_cit28","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1053\/meta.2002.32022","article-title":"The human amylin analog, pramlintide,\ncorrects postprandial hyperglucagonemia in patients with type I diabetes","volume":"51","author":"Fineman","year":"2002","journal-title":"Metabolism"},{"key":"2026090316254150400_cit29","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1345\/aph.1C387","article-title":"Pramlintide for the treatment of diabetes mellitus","volume":"37","author":"Kleppinger","year":"2003","journal-title":"Ann. Pharmacother."},{"key":"2026090316254150400_cit30","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.2337\/diabetes.53.suppl_3.S233","article-title":"Amylin agonists: A novel approach in the treatment of diabetes","volume":"53","author":"Schmitz","year":"2004","journal-title":"Diabetes"},{"key":"2026090316254150400_cit31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.brainres.2011.12.022","article-title":"Amylin\u2013leptin\ncoadministration stimulates central histaminergic signaling in rats","volume":"1442","author":"Seth","year":"2012","journal-title":"Brain Res."},{"key":"2026090316254150400_cit32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/oby.2009.187","article-title":"Interaction\nof leptin and amylin in the long-term maintenance of weight loss in\ndiet-induced obese rats","volume":"18","author":"Trevaskis","year":"2010","journal-title":"Obesity"},{"key":"2026090316254150400_cit33","doi-asserted-by":"crossref","first-page":"7257","DOI":"10.1073\/pnas.0706473105","article-title":"Leptin responsiveness restored by\namylin agonism in\ndiet-induced obesity: Evidence from nonclinical and clinical studies","volume":"105","author":"Roth","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090316254150400_cit34","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1021\/ol047480+","article-title":"Incorporation of pseudoproline derivatives allows the\nfacile synthesis of human IAPP, a highly amyloidogenic and aggregation-prone\npolypeptide","volume":"7","author":"Abedini","year":"2005","journal-title":"Org. Lett."},{"key":"2026090316254150400_cit35","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":"2026090316254150400_cit36","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":"2026090316254150400_cit37","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":"2026090316254150400_cit38","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1021\/bi401164k","article-title":"pH dependence\nof amylin fibrillization","volume":"53","author":"Jha","year":"2014","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit39","doi-asserted-by":"crossref","first-page":"14588","DOI":"10.1021\/bi00044a038","article-title":"Effect of\npH and insulin\non fibrillogenesis of islet amyloid polypeptide in-vitro","volume":"34","author":"Charge","year":"1995","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit40","doi-asserted-by":"crossref","first-page":"14340","DOI":"10.1021\/ja1046186","article-title":"Combination of kinetically selected\ninhibitors in trans leads to highly effective inhibition of amyloid\nformation","volume":"132","author":"Meng","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026090316254150400_cit41","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1021\/bi981658g","article-title":"Effects of sequential\nproline substitutions on amyloid\nformation by human amylin20\u201329","volume":"38","author":"Moriarty","year":"1999","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit42","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 of \u03b2-cell death","volume":"47","author":"Meng","year":"2008","journal-title":"Biochemistry"},{"key":"2026090316254150400_cit43","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.jmb.2011.12.032","article-title":"Sensitivity of amyloid\nformation by human islet amyloid polypeptide to mutations at residue\n20","volume":"421","author":"Cao","year":"2012","journal-title":"J. Mol. Biol."},{"key":"2026090316254150400_cit44","doi-asserted-by":"crossref","first-page":"10378","DOI":"10.1002\/anie.201302840","article-title":"Selectively\nN-methylated soluble IAPP mimics as potent IAPP receptor agonists\nand nanomolar inhibitors of cytotoxic self-assembly of both IAPP and\nA\u03b240","volume":"52","author":"Yan","year":"2013","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090316254150400_cit45","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1073\/pnas.0507471103","article-title":"Design of\na mimic of nonamyloidogenic and bioactive\nhuman islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor\nof IAPP cytotoxic fibrillogenesis","volume":"103","author":"Yan","year":"2006","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi500592p","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/37\/5876\/7903385\/bi500592p.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/37\/5876\/7903385\/bi500592p.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T20:25:57Z","timestamp":1788467157000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/37\/5876\/775226\/Rationally-Designed-Nontoxic-Nonamyloidogenic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,20]]},"references-count":45,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2014,8,20]]},"published-print":{"date-parts":[[2014,9,23]]}},"URL":"https:\/\/doi.org\/10.1021\/bi500592p","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,20]]}}}