{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:16:59Z","timestamp":1788430619274,"version":"build-2803163510"},"reference-count":189,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2025-06834"],"award-info":[{"award-number":["RGPIN-2025-06834"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The islet amyloid polypeptide (IAPP) is a peptide hormone playing key biological roles, including glucose homeostasis and regulation of food intake, conferring high therapeutic potential to treat metabolic disorders. Nonetheless, IAPP is mainly known as the major component of the amyloid fibrils observed in the pancreatic islets of patients afflicted with type 2 diabetes, and the accumulation of these insoluble protein deposits correlates closely with the loss of pancreatic \u03b2-cells. The inherent aggregation propensity of this peptide hormone is not only associated with the pathogenesis of type 2 diabetes but also complicates the design of IAPP derivatives for the treatment of metabolic disorders. Accordingly, elucidating the molecular mechanisms by which IAPP self-assembles into amyloid fibrils is critical to identify chemical strategies to arrest aggregation, as well as to design safe and stable IAPP-derived therapeutics. This review aims at presenting the different mechanistic models of IAPP aggregation and how to exploit this information to identify inhibitors of amyloid formation and non-aggregating peptide agonists. After discussing the conformational conversions allowing IAPP to undergo a mainly disordered monomeric conformation into ordered cross-\u03b2-sheet quaternary supramolecular structures, we present chemical strategies to prevent amyloid deposition and to develop non-aggregating peptide-based therapeutics.<\/jats:p>","DOI":"10.3390\/ijms27062598","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:23:03Z","timestamp":1773307383000},"page":"2598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Mechanisms of Islet Amyloid Polypeptide Aggregation: Towards Chemical Strategies to Prevent Amyloid Formation and to Design Non-Aggregating Peptide Therapeutics"],"prefix":"10.3390","volume":"27","author":[{"given":"C\u00e9cile","family":"Bousch","sequence":"first","affiliation":[{"name":"Department of Chemistry, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, C.P. 8888, Succursale Centre-Ville, Montreal, QC H3C 3P8, Canada"},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Montreal, QC H2X 3Y7, Canada"},{"name":"BioCIS, CNRS, Universit\u00e9 Paris Saclay, 17 Avenue des Sciences, B\u00e2timent Henri Moissan, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"B\u00e9rub\u00e9","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, C.P. 8888, Succursale Centre-Ville, Montreal, QC H3C 3P8, Canada"},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Montreal, QC H2X 3Y7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaryta","family":"Babych","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, C.P. 8888, Succursale Centre-Ville, Montreal, QC H3C 3P8, Canada"},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Montreal, QC H2X 3Y7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Ongeri","sequence":"additional","affiliation":[{"name":"BioCIS, CNRS, Universit\u00e9 Paris Saclay, 17 Avenue des Sciences, B\u00e2timent Henri Moissan, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-8787","authenticated-orcid":false,"given":"Steve","family":"Bourgault","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, C.P. 8888, Succursale Centre-Ville, Montreal, QC H3C 3P8, Canada"},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Montreal, QC H2X 3Y7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17243","DOI":"10.1016\/S0021-9258(19)77825-9","article-title":"An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing","volume":"263","author":"Sanke","year":"1988","journal-title":"J. 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