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However, its aggregation and deposition in the pancreatic islets are associated with type 2 diabetes. While this peptide adopts mainly a random coil structure in solution, its secondary conformational conversion into \u03b1-helix represents a critical step for receptor activation and contributes to amyloid formation and associated cytotoxicity. Considering the large conformational landscape and high amyloidogenicity of the peptide, as well as the complexity of the self-assembly process, it is challenging to delineate the delicate interplay between helical folding, peptide aggregation, and receptor activation. In the present study, we probed the roles of helical folding on the function-toxicity duality of IAPP by restricting its conformational ensemble through side chain-to-side chain stapling via azide\u2013alkyne cycloaddition. Intramolecular macrocyclization (i; i + 4) constrained IAPP into \u03b1-helix and inhibited its aggregation into amyloid fibrils. These helical derivatives slowed down the self-assembly of unmodified IAPP. Site-specific macrocyclization modulated the capacity of IAPP to perturb lipid bilayers and cell plasma membrane and reduced, or even fully inhibited, the cytotoxicity associated with aggregation. Furthermore, the \u03b1-helical IAPP analogs showed moderate to high potency toward cognate G protein-coupled receptors. Overall, these results indicate that macrocyclization represents a promising strategy to protect an amyloidogenic peptide hormone from aggregation and associated toxicity, while maintaining high receptor activity.<\/jats:p>","DOI":"10.1021\/jacs.4c05297","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T10:02:31Z","timestamp":1725357751000},"page":"25513-25526","source":"Crossref","is-referenced-by-count":13,"title":["Converting\nthe Amyloidogenic Islet Amyloid Polypeptide\ninto a Potent Nonaggregating Peptide Ligand by Side Chain-to-Side\nChain Macrocyclization"],"prefix":"10.1021","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9559-529X","authenticated-orcid":true,"given":"Margaryta","family":"Babych","sequence":"first","affiliation":[{"name":"Universite\u0301 du Que\u0301bec a\u0300 Montre\u0301al , , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5332-1236","authenticated-orcid":true,"given":"Michael L.","family":"Garelja","sequence":"additional","affiliation":[{"name":"University of Otago , , 18 Frederick Street , ,","place":["Dunedin, New Zealand, 9016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9824-665X","authenticated-orcid":true,"given":"Phuong Trang","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Universite\u0301 du Que\u0301bec a\u0300 Montre\u0301al , , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9558-5122","authenticated-orcid":true,"given":"Debbie L.","family":"Hay","sequence":"additional","affiliation":[{"name":"University of Otago , , 18 Frederick Street , ,","place":["Dunedin, New Zealand, 9016"]},{"name":"University of Auckland , , 3A Symonds Street , ,","place":["Auckland, New Zealand, 92019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-8787","authenticated-orcid":true,"given":"Steve","family":"Bourgault","sequence":"additional","affiliation":[{"name":"Universite\u0301 du Que\u0301bec a\u0300 Montre\u0301al , , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]},{"name":"Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO , C.P. 8888, Succursale Centre-Ville , ,","place":["Montre\u0301al, Canada, H3C 3P8"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2024,9,3]]},"reference":[{"issue":"3","key":"2026101614071723600_cit1","doi-asserted-by":"publisher","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":"2026101614071723600_cit2","doi-asserted-by":"publisher","first-page":"105965","DOI":"10.1016\/j.appet.2022.105965","article-title":"Creating\nthe amylin story","volume":"172","author":"Lutz","year":"2022","journal-title":"Appetite"},{"issue":"1\u20133","key":"2026101614071723600_cit3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S0167-0115(02)00252-5","article-title":"Islet amyloid\npolypeptide inhibits glucagon release and exerts a dual action on\ninsulin release from isolated islets","volume":"111","author":"Akesson","year":"2003","journal-title":"Regul.\nPept."},{"issue":"3","key":"2026101614071723600_cit4","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1124\/pr.115.010629","article-title":"Amylin:\nPharmacology, Physiology, and Clinical Potential","volume":"67","author":"Hay","year":"2015","journal-title":"Pharmacol. Rev."},{"issue":"1","key":"2026101614071723600_cit5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bph.14075","article-title":"Update on the pharmacology\nof calcitonin\/CGRP family of peptides: IUPHAR Review 25","volume":"175","author":"Hay","year":"2018","journal-title":"Br. J. Pharmacol."},{"issue":"2","key":"2026101614071723600_cit6","doi-asserted-by":"publisher","first-page":"355","DOI":"10.2147\/vhrm.s1978","article-title":"Pramlintide, the synthetic analogue\nof amylin: physiology, pathophysiology, and effects on glycemic control,\nbody weight, and selected biomarkers of vascular risk","volume":"4","author":"Hoogwerf","year":"2008","journal-title":"Vasc. Health Risk Manag."},{"issue":"3","key":"2026101614071723600_cit7","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1124\/jpet.121.000567","article-title":"AM833 Is a Novel Agonist of Calcitonin\nFamily G Protein-Coupled Receptors: Pharmacological Comparison with\nSix Selective and Nonselective Agonists","volume":"377","author":"Fletcher","year":"2021","journal-title":"J.\nPharmacol. Exp. 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Biol."},{"issue":"2","key":"2026101614071723600_cit17","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1039\/C7SC03789A","article-title":"Site-specific detection of protein secondary structure\nusing 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric\nhIAPP","volume":"9","author":"Maj","year":"2018","journal-title":"Chem. Sci."},{"issue":"15","key":"2026101614071723600_cit18","doi-asserted-by":"publisher","first-page":"155101","DOI":"10.1063\/1.4798460","article-title":"\u03b1-helix to\n\u03b2-hairpin transition of human amylin monomer","volume":"138","author":"Singh","year":"2013","journal-title":"J. Chem. 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Chem. Res."},{"issue":"9","key":"2026101614071723600_cit22","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1016\/j.bbamem.2018.03.014","article-title":"Molecular mechanisms of membrane-associated amyloid\naggregation: Computational perspective and challenges","volume":"1860","author":"Press-Sandler","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"issue":"48","key":"2026101614071723600_cit23","doi-asserted-by":"publisher","first-page":"14383","DOI":"10.1002\/anie.201507092","article-title":"Delineating\nthe Role of Helical Intermediates in Natively Unfolded Polypeptide\nAmyloid Assembly and Cytotoxicity","volume":"54","author":"De Carufel","year":"2015","journal-title":"Angew. Chem.,\nInt. Ed. Engl."},{"issue":"5","key":"2026101614071723600_cit24","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1021\/jacs.8b08537","article-title":"Misfolding of a Human\nIslet Amyloid Polypeptide at the Lipid Membrane Populates through\n\u03b2-Sheet Conformers without Involving \u03b1-Helical Intermediates","volume":"141","author":"Tan","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071723600_cit25","doi-asserted-by":"publisher","first-page":"44041","DOI":"10.1038\/srep44041","article-title":"The redox environment triggers conformational changes and aggregation\nof hIAPP in Type II Diabetes","volume":"7","author":"Rodriguez Camargo","year":"2017","journal-title":"Sci. Rep."},{"issue":"4","key":"2026101614071723600_cit26","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1002\/1097-0282(20010405)58:4&lt;422::AID-BIP1018&gt;3.0.CO;2-T","article-title":"A helical capping\nmotif in ShK toxin and its role in helix stabilization","volume":"58","author":"Lanigan","year":"2001","journal-title":"Biopolymers"},{"issue":"50","key":"2026101614071723600_cit27","doi-asserted-by":"publisher","first-page":"16066","DOI":"10.1021\/jp409755y","article-title":"Molecular\nsimulations indicate marked\ndifferences in the structure of amylin mutants, correlated with known\naggregation propensity","volume":"117","author":"Miller","year":"2013","journal-title":"J. Phys. Chem. B"},{"issue":"12","key":"2026101614071723600_cit28","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1111\/bph.13496","article-title":"Amylin structure-function\nrelationships and receptor\npharmacology: implications for amylin mimetic drug development","volume":"173","author":"Bower","year":"2016","journal-title":"Br. J. Pharmacol."},{"issue":"6587","key":"2026101614071723600_cit29","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm9609","article-title":"A structural basis for amylin receptor\nphenotype","volume":"375","author":"Cao","year":"2022","journal-title":"Science"},{"issue":"10","key":"2026101614071723600_cit30","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1016\/j.bbamem.2011.06.012","article-title":"Structure\nand membrane orientation of IAPP in its natively amidated form at\nphysiological pH in a membrane environment","volume":"1808","author":"Nanga","year":"2011","journal-title":"Biochim. Biophys. 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Biol. Chem."},{"issue":"3","key":"2026101614071723600_cit34","doi-asserted-by":"publisher","first-page":"6241","DOI":"10.3390\/ijms14036241","article-title":"Adsorption and Orientation\nof Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid\nBilayers: Implications for Membrane-Mediated Aggregation","volume":"14","author":"Jia","year":"2013","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"2026101614071723600_cit35","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1110\/ps.062486907","article-title":"Direct detection of transient \u03b1-helical states\nin islet amyloid polypeptide","volume":"16","author":"Williamson","year":"2007","journal-title":"Protein Sci."},{"issue":"21","key":"2026101614071723600_cit36","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1002\/cbic.201700352","article-title":"Effect of Stapling\nArchitecture on Physiochemical Properties and\nCell Permeability of Stapled \u03b1-Helical Peptides: A Comparative\nStudy","volume":"18","author":"Tian","year":"2017","journal-title":"Chembiochem"},{"issue":"20","key":"2026101614071723600_cit37","doi-asserted-by":"publisher","first-page":"3654","DOI":"10.3390\/molecules24203654","article-title":"Stapled Peptides-A\nUseful Improvement\nfor Peptide-Based Drugs","volume":"24","author":"Moiola","year":"2019","journal-title":"Molecules"},{"issue":"1","key":"2026101614071723600_cit38","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1021\/acsptsci.8b00002","article-title":"Molecular Signature for Receptor\nEngagement in the Metabolic Peptide Hormone Amylin","volume":"1","author":"Bower","year":"2018","journal-title":"ACS Pharmacol. 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Chem."},{"issue":"5868","key":"2026101614071723600_cit43","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1126\/science.1154470","article-title":"Coiled-coil irregularities\nand instabilities\nin group A Streptococcus M1 are required for virulence","volume":"319","author":"McNamara","year":"2008","journal-title":"Science"},{"issue":"13","key":"2026101614071723600_cit44","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/bip.360311304","article-title":"Parameters\nof helix-coil transition theory for alanine-based peptides of varying\nchain lengths in water","volume":"31","author":"Scholtz","year":"1991","journal-title":"Biopolymers"},{"key":"2026101614071723600_cit45","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ab.2017.06.007","article-title":"Thioflavin\nT fluorescence to analyse\namyloid formation kinetics: Measurement frequency as a factor explaining\nirreproducibility","volume":"532","author":"Sebastiao","year":"2017","journal-title":"Anal. Biochem."},{"key":"2026101614071723600_cit46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bpc.2016.09.007","article-title":"Amyloidogenesis\nof the amylin analogue pramlintide","volume":"219","author":"da Silva","year":"2016","journal-title":"Biophys.\nChem."},{"issue":"6","key":"2026101614071723600_cit47","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.chembiol.2014.05.007","article-title":"Folded small molecule\nmanipulation of islet amyloid polypeptide","volume":"21","author":"Kumar","year":"2014","journal-title":"Chem.\nBiol."},{"key":"2026101614071723600_cit48","doi-asserted-by":"publisher","first-page":"11412","DOI":"10.1038\/ncomms11412","article-title":"Foldamer-mediated\nmanipulation of a pre-amyloid toxin","volume":"7","author":"Kumar","year":"2016","journal-title":"Nat. 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