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

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) faces challenges in achieving cell selectivity for therapeutic applications.
• Pancreatic beta cells are accessible but difficult to target selectively for drug delivery.
• The glucagon-like peptide-1 receptor (GLP-1R) offers a potential route for beta-cell-specific targeting.

Purpose of the Study:

• To develop a novel PROTAC system for selective protein degradation in pancreatic beta cells.
• To utilize the GLP-1R as a targeting mechanism for beta-cell-specific drug delivery.
• To create a conformationally stabilized GLP-1 analogue for enhanced receptor binding and conjugation.

Main Methods:

• Synthesized a multicomponent stapled GLP-1 analogue using tryptophan-mediated multicomponent Petasis reaction (TMPR).
• Conjugated the stabilized GLP-1 analogue to a bromodomain-containing protein 4 (BRD4)-directed degrader to create a GLP-1-guided PROTAC.
• Evaluated the PROTAC's GLP-1R agonism, receptor-guided uptake, and selective BRD4 degradation in GLP-1R-positive cells.

Main Results:

• Developed a modular stapling strategy yielding a stabilized GLP-1 peptide with enhanced alpha-helicity and receptor potency.
• Constructed the first GLP-1-guided PROTAC, demonstrating retained GLP-1R agonism.
• Achieved selective BRD4 degradation in GLP-1R-positive cells, confirming receptor-guided delivery and activation.

Conclusions:

• A TMPR-stapled GLP-1 peptide serves as an effective beta-cell-directed delivery platform for receptor-defined protein degradation.
• This approach provides a proof-of-concept for targeted protein degradation in specific cell populations.
• The developed GLP-1-guided PROTAC advances the potential of PROTACs as therapeutics for diseases involving pancreatic beta cells.