Cyclic Peptides Modulating Metabolic Activity via Selective Binding
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Solution Overview
Problem
There is a need for new ligands, particularly selective ligands, for the melanocortin receptors and the Kir7.1 K+ ion channel, which are involved in pathways related to food intake and energy homeostasis, as existing ligands do not effectively address obesity and related metabolic issues.
Innovation Solution
Development of cyclic peptides that act as melanocortin ligands and Kir7.1 ligands, specifically compounds of formula I, which modulate the activity of melanocortin receptors and Kir7.1 ion channels, thereby influencing metabolic activity and appetite.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ligands are used for melanocortin receptors, then the basic pathway engagement is achieved, but the selectivity and effectiveness for obesity treatment is insufficient
Solution Approach 1:
The patent applies local quality by introducing specific amino acid residues at particular positions within the cyclic peptide structure. Key positions include X1 (Arg or DArg), X2 (Phe or DPhe), and X3 (Phe, DPhe, or hPhe), which create localized interaction zones that enhance selectivity for MC4R and Kir7.1 while maintaining overall structural integrity. This localized optimization of binding properties resolves the contradiction between selectivity and therapeutic effectiveness.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences, cyclic peptide size (8-13 residues), and stereochemistry (L/D proline configurations) to optimize ligand properties. These parameter adjustments enable fine-tuning of binding affinity and selectivity for specific receptors, thereby improving both reliability of binding and adaptability for obesity treatment while avoiding the limitations of existing ligands.
2Reliability
If cyclic peptides are designed to engage MC4R and Kir7.1 pathways, then therapeutic potential for obesity is enhanced, but the complexity of ligand design increases
Solution Approach 1:
The patent applies universality by designing cyclic peptides that can simultaneously engage both MC4R and Kir7.1 pathways. The core structure with specific amino acid motifs (particularly Arg-Phe-Phe at positions X1-X3) enables dual functionality, allowing a single ligand design to address multiple aspects of energy homeostasis and food intake regulation, thereby enhancing therapeutic potential without proportionally increasing design complexity.
Solution Approach 2:
The patent uses segmentation by dividing the cyclic peptide into functional domains: a core structure (Pro-X1-X2-X3-X4-X5-DPro) that provides structural stability, and variable regions (X1-X6) that mediate specific receptor interactions. This segmentation allows independent optimization of different functional requirements, managing design complexity while achieving reliable therapeutic effects through modular design.
3Manufacturing precision
If selective ligands are developed for melanocortin receptors, then metabolic activity modulation is improved, but the difficulty of achieving both MC4R and Kir7.1 engagement increases
Solution Approach 1:
The patent applies the intermediary principle by using the cyclic peptide structure itself as a mediator that bridges MC4R and Kir7.1 engagement. The specific amino acid sequence and cyclic conformation act as an intermediary mechanism that simultaneously satisfies both receptor binding requirements, simplifying the detection and measurement of dual engagement compared to using separate ligands for each target.
Solution Approach 2:
The patent employs composite materials by creating a hybrid ligand structure that combines features necessary for both MC4R and Kir7.1 binding. The cyclic peptide incorporates multiple functional motifs (basic residues for ionic interactions, aromatic residues for pi-stacking, hydrophilic/hydrophobic regions) within a single molecular framework, achieving precise metabolic modulation through composite structural elements rather than separate components.
Data Source
AI summary
Certain embodiments of the invention provide a cyclic compound of formula I:wherein: Pro is a residue of L-proline; X1 is a residue of Arg or DArg; X2 is a residue of Phe or DPhe; X3 is a residue of Phe, DPhe or hPhe; X4 is a residue of a natural or unnatural amino acid; X5 is a residue of Ala, Asp, Glu, Lys, His, Phe, Ser, Leu or Gly; X6 is a residue of Phe, Ala, Gly, Ser, Lys, Asp, Leu, Nle, Trp, Tyr, Cha or hPhe; and DPro is a residue of D-proline; or a salt thereof. Certain embodiments also provide compositions comprising such compounds, as well as methods of using such compounds and compositions.