Multicomponent Stapling of Glucagon-Like Peptide-1 Enables Receptor-Guided PROTAC Delivery.
This study presents a novel chemical strategy for delivering protein-degrading molecules (PROTACs) selectively to pancreatic β-cells by exploiting the glucagon-like peptide-1 receptor (GLP-1R). The researchers engineered a modified GLP-1 peptide using a tryptophan-mediated multicomponent Petasis reaction (TMPR), a modular "stapling" technique that locks the peptide into a stable α-helical conformation. This stapled analogue was reported to show enhanced structural stability and improved GLP-1R potency compared with the wild-type peptide. The stapling strategy also incorporated a chemical handle allowing conjugation to a PROTAC — a bifunctional molecule designed to degrade bromodomain-containing protein 4 (BRD4), a transcriptional regulator implicated in various diseases. The resulting GLP-1–PROTAC conjugate reportedly retained GLP-1R agonist activity and selectively induced BRD4 degradation in GLP-1R-expressing cells, consistent with receptor-mediated uptake and intracellular degrader activation. The study was conducted entirely in cellular (in vitro) systems; no animal or human data were reported. Key limitations include the absence of in vivo validation, and the translational relevance to human β-cell biology remains to be established.
Why this grade: All experiments were performed in cell-based systems with no animal models or human subjects, limiting conclusions to proof-of-concept in vitro findings.
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.
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