Dual-Stapled Peptide Agonists for Glucose Control With Lower Hypoglycemia Risk
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Solution Overview
Problem
Current treatments for diabetes, particularly type 2 diabetes, are inadequate in effectively managing glucose/lipid metabolism and weight, leading to high risks of complications such as diabetic nephropathy, retinopathy, and foot ulcers, with existing incretin-based therapies posing risks of hypoglycemia.
Innovation Solution
Development of a polypeptide with specific sequences that act as agonists for GLP-1R and GIPR, enhancing glucose/lipid metabolism regulation and weight management, formulated as a pharmaceutical composition for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing incretin-based therapies are used to manage glucose metabolism, then glucose control is improved, but the risk of hypoglycemia increases
Solution Approach 1:
The patent applies local quality by designing a dual-stapled peptide structure where specific amino acid residues are modified with different stapling chemistries at different positions. The peptide contains two distinct stapling regions: one stapling a Glu-Lys pair and another stapling a Lys-Glu pair, with each staple having different structural characteristics. This localized modification approach allows the peptide to maintain high affinity for both GLP-1R and GIPR receptors while improving metabolic stability and reducing hypoglycemia risk, as evidenced by the compound's ability to achieve potent glucose-lowering effects without proportionally increasing hypoglycemia incidence.
2Reliability
If triple activation of GIPR, GLP-1R, and GCGR is achieved, then synergistic effect on glucose/lipid metabolism is improved, but the complexity of the therapeutic approach increases
Solution Approach 1:
The patent merges multiple therapeutic functions into a single dual-stapled peptide molecule that simultaneously activates GLP-1R and GIPR receptors. By incorporating two disulfide staples into one peptide structure, the invention achieves synergistic glucose and lipid metabolism regulation through coordinated receptor activation, eliminating the need for multiple separate therapies. This is demonstrated by the compound's ability to produce both glucose-lowering and lipid-lowering effects through a single agent, simplifying the treatment regimen while maintaining comprehensive metabolic control.
3Duration of action of stationary object
If peptide stability is enhanced through structural modification, then duration of action is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-forming two disulfide staples within the peptide structure during synthesis, which lock the peptide into a stable conformation before administration. The dual-stapling approach is incorporated into the peptide's primary structure design, where the staple-forming amino acid pairs (Glu-Lys and Lys-Glu) are positioned to create rigidified regions that enhance metabolic stability. This pre-structured approach allows the peptide to resist proteolytic degradation and maintain prolonged circulation half-life, as demonstrated by the extended duration of action observed in preclinical studies, while the modular synthesis approach keeps manufacturing complexity manageable.
Data Source
AI summary
A series of stapled peptides and a use thereof, specifically relating to a polypeptide having a sequence as shown in a formulas (I-1)-(I-5) and (II-6), and a pharmaceutically acceptable salt thereof.