Hydantoin-Modified Cyclic Peptides for MC-4 Receptor Selectivity
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Solution Overview
Problem
Current melanocortin receptor ligands lack selectivity and stability for the MC-4 receptor subtype, which is crucial for treating various diseases related to body weight and metabolic disorders, and they have limited efficacy in modulating melanocortin receptor activities.
Innovation Solution
Development of cyclic peptide analogs modified with a hydantoin moiety, incorporating unnatural amino acid residues, which exhibit high affinity and selectivity for the MC-4 receptor subtype, leading to prolonged plasma half-life and effective suppression of food intake and body weight loss.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional melanocortin receptor ligands are used, then general melanocortin receptor activity is modulated, but selectivity for MC-4 receptor subtype is insufficient
Solution Approach 1:
The patent applies local quality by modifying specific regions of the melanocortin ligand structure. The N-terminal region is replaced with unnatural amino acid residues, and a cyclic structure is introduced at the C-terminal end. These localized modifications create specific interactions with the MC-4 receptor subtype, achieving high selectivity while maintaining binding affinity.
Solution Approach 2:
The patent employs parameter changes by altering the chemical properties of the ligand through incorporation of unnatural amino acids (such as D-amino acids, N-methylated amino acids) and cyclic structures. These parameter changes in molecular rigidity, hydrophobicity, and steric configuration enable selective binding to MC-4 receptor while preserving overall receptor activation capability.
2Reliability
If conventional melanocortin receptor ligands are used, then receptor modulation activity is achieved, but plasma half-life is limited
Solution Approach 1:
The patent applies inversion by using D-amino acids instead of the conventional L-amino acids in the peptide structure. This inversion of stereochemistry protects the peptide from degradation by conventional proteases in the plasma, thereby extending the plasma half-life while maintaining receptor binding activity through the preserved key pharmacophore elements.
Solution Approach 2:
The patent creates a composite structure by combining unnatural amino acid residues with cyclic peptide backbone. This composite design integrates the stability of cyclic structures with the functional properties of amino acid side chains, resulting in a ligand that resists enzymatic degradation and maintains prolonged pharmacological activity in plasma.
3Reliability
If selective MC-4 receptor ligands are developed, then efficacy in weight loss and metabolic disorders is improved, but structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the ligand into distinct functional segments: an N-terminal region with unnatural amino acids for selectivity, a central cyclic structure for stability and receptor engagement, and a C-terminal region for receptor activation. This segmentation allows each part to contribute specifically to the overall therapeutic efficacy while maintaining a manageable structural framework.
Data Source
AI summary
The present invention relates to peptide ligands of the melanocortin receptors, in particular the melanocortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and sexual dysfunction.