Multicomponent stapled GLP-1 analogue enables receptor-guided PROTAC delivery for selective BRD4 degradation

Translating proteolysis-targeting chimeras (PROTACs) into therapeutics faces significant hurdles, primarily due to challenges in achieving cell-selective targeted protein degradation, unfavorable pharmacokinetic properties, and systemic toxicity. While pancreatic β-cells are highly vascularized and accessible to circulating peptides, developing selective receptor-mediated drug delivery remains a key challenge. Exploiting the glucagon-like peptide-1 receptor (GLP-1R) offers a promising avenue for β-cell-specific entry, providing a potential solution to enhance PROTAC selectivity and reduce off-target effects, which this study aims to address.

Researchers developed a novel multicomponent stapling strategy using a tryptophan-mediated multicomponent Petasis reaction (TMPR) to construct a conformationally stabilized glucagon-like peptide-1 (GLP-1) analogue. This modular approach provided a peptide with an orthogonal handle for late-stage conjugation. They then linked this improved GLP-1 analogue to a bromodomain-containing protein 4 (BRD4)-directed degrader, creating the first GLP-1-guided PROTAC. The resulting conjugate was evaluated for GLP-1R agonism and its ability to induce selective BRD4 degradation in GLP-1R-positive cells, assessing receptor-guided uptake and intracellular payload activation.

The novel TMPR-stapled GLP-1 analogue exhibited markedly enhanced α-helicity and improved receptor potency compared to the wild-type peptide. This conformational stabilization proved crucial for its function. When conjugated to a BRD4-directed degrader, the resulting GLP-1-guided PROTAC successfully retained its GLP-1R agonism, indicating that the conjugation did not compromise the peptide's primary receptor binding capabilities. Critically, this PROTAC induced selective BRD4 degradation exclusively in GLP-1R-positive cells. This selectivity was consistent with receptor-guided uptake and subsequent intracellular activation of the degrader payload. This represents a significant step towards targeted protein degradation. > This work provides 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, opening new avenues for highly specific therapeutic interventions.