{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:03:01Z","timestamp":1789844581565,"version":"4.0.1"},"reference-count":32,"publisher":"Wiley","issue":"34","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["GA CR 22\u201307138O"],"award-info":[{"award-number":["GA CR 22\u201307138O"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,8,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Achieving cell\u2010selective targeted protein degradation remains a major challenge for translating proteolysis\u2010targeting chimeras (PROTACs) into therapeutics. Although pancreatic \u03b2\u2010cells are well vascularised and readily accessible to circulating peptides, selective receptor\u2010mediated drug delivery remains challenging. Here, we exploit the glucagon\u2010like peptide\u20101 receptor (GLP\u20101R) as a \u03b2\u2010cell\u2010specific entry route and report, for the first time, a multicomponent stapled glucagon\u2010like peptide\u20101 (GLP\u20101) analogue constructed by tryptophan\u2010mediated multicomponent Petasis reaction (TMPR). This modular stapling strategy affords a conformationally stabilised GLP\u20101 peptide bearing a chemically orthogonal handle for late\u2010stage conjugation, displaying markedly enhanced \u03b1\u2010helicity and improved receptor potency, compared with the wild\u2010type peptide. Linking this improved analogue to a bromodomain\u2010containing protein 4 (BRD4)\u2010directed degrader furnishes the first GLP\u20101\u2010guided PROTAC, which retains GLP\u20101R agonism and induces selective BRD4 degradation in GLP\u20101R\u2010positive cells, consistent with receptor\u2010guided uptake and intracellular activation of the degrader payload. Together, these results provide strong proof\u2010of\u2010concept evidence that a TMPR\u2010stapled GLP\u20101 peptide can serve as a \u03b2\u2010cell\u2010directed delivery platform for receptor\u2010defined protein degradation.<\/jats:p>","DOI":"10.1002\/anie.9595531","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T10:53:29Z","timestamp":1781261609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multicomponent Stapling of Glucagon\u2010Like Peptide\u20101 Enables Receptor\u2010Guided PROTAC Delivery"],"prefix":"10.1002","volume":"65","author":[{"given":"Jan L.","family":"Venne","sequence":"first","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"AstraZeneca Plc Cambridge Biomedical Campus 1 Francis Crick Avenue  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-2360","authenticated-orcid":false,"given":"Sona","family":"Krajcovicova","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"Department of Organic Chemistry Palacky University Olomouc  Olomouc Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Davies","sequence":"additional","affiliation":[{"name":"AstraZeneca Plc Cambridge Biomedical Campus 1 Francis Crick Avenue  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Bolt","sequence":"additional","affiliation":[{"name":"AstraZeneca Plc Cambridge Biomedical Campus 1 Francis Crick Avenue  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson","family":"Revell","sequence":"additional","affiliation":[{"name":"AstraZeneca Plc Cambridge Biomedical Campus 1 Francis Crick Avenue  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7355-2824","authenticated-orcid":false,"given":"David R.","family":"Spring","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/onco5040047"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009\u20101082"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(13)70049\u20104"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.110.085142"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102782"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2024.1940"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c12043"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aat3386"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3009"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00285"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00141A"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.10.044"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00308"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202307782"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.4c00298"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.396"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rechem.2025.102670"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500810s"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(17)37366\u20100"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00726"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01553"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2012.00141"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b00216"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2329"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4RA01974A"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02123"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202505659"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.6.1237"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010022\u201000529\u2010w"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.443"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2018.12.032"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.9595531","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.9595531","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.9595531","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:27:11Z","timestamp":1789842431000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.9595531"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":32,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2026,8,17]]}},"alternative-id":["10.1002\/anie.9595531"],"URL":"https:\/\/doi.org\/10.1002\/anie.9595531","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]},"assertion":[{"value":"2026-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e9595531"}}