Multicomponent Stapling of Glucagon‐Like Peptide‐1 Enables Receptor‐Guided PROTAC Delivery

Achieving cell‐selective targeted protein degradation remains a major challenge for translating proteolysis‐targeting chimeras (PROTACs) into therapeutics. Although pancreatic β‐cells are well vascularised and readily accessible to circulating peptides, selective receptor‐mediated drug delivery remains challenging. Here, we exploit the glucagon‐like peptide‐1 receptor (GLP‐1R) as a β‐cell‐specific entry route and report, for the first time, a multicomponent stapled glucagon‐like peptide‐1 (GLP‐1) analogue constructed by tryptophan‐mediated multicomponent Petasis reaction (TMPR). This modular stapling strategy affords a conformationally stabilised GLP‐1 peptide bearing a chemically orthogonal handle for late‐stage conjugation, displaying markedly enhanced α‐helicity and improved receptor potency, compared with the wild‐type peptide. Linking this improved analogue to a bromodomain‐containing protein 4 (BRD4)‐directed degrader furnishes the first GLP‐1‐guided PROTAC, which retains GLP‐1R agonism and induces selective BRD4 degradation in GLP‐1R‐positive cells, consistent with receptor‐guided uptake and intracellular activation of the degrader payload. Together, these results provide strong proof‐of‐concept evidence that a TMPR‐stapled GLP‐1 peptide can serve as a β‐cell‐directed delivery platform for receptor‐defined protein degradation.