Cyclic Peptides for MC4-R Selectivity
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Solution Overview
Problem
Despite significant scientific and pharmaceutical interest, no melanocortin receptor-specific peptide has been approved as a drug for any therapeutic indication, and none have advanced past Phase II clinical trials, indicating a need for effective melanocortin receptor-specific peptides for pharmaceutical applications.
Innovation Solution
Development of cyclic peptides, including specific structural formulas and pharmaceutical compositions, that act as selective MC4-R ligands for treating sexual dysfunction, obesity, and other melanocortin receptor-mediated disorders, with agonist properties to modulate energy homeostasis and other functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If melanocortin receptor-specific peptides are developed for therapeutic use, then treatment efficacy for obesity and sexual dysfunction is improved, but clinical advancement beyond Phase II trials has not been achieved
Solution Approach 1:
The patent applies parameter changes by modifying the peptide structure through cyclic conformation and specific amino acid substitutions (e.g., Nle4, D-Phe7, Lys10) to optimize receptor binding affinity and selectivity. These structural parameter changes enable the peptides to achieve therapeutic efficacy while overcoming limitations of linear peptides that prevented clinical advancement.
Solution Approach 2:
The invention uses composite peptide structures combining multiple modified amino acids within a cyclic framework. This composite approach integrates N-terminal acylation, cyclic lactam bridges, and specific residue substitutions to create a synergistic structure that enhances both potency and selectivity for MC4-R, addressing the clinical trial stagnation issue.
2Measurement precision
If selective MC4-R ligand specificity is increased to treat obesity and sexual dysfunction, then therapeutic precision is improved, but potential off-target effects on other melanocortin receptors may worsen
Solution Approach 1:
The patent applies local quality by introducing specific modifications at particular positions within the peptide sequence. For example, the cyclic structure is formed between specific residues (Asp5 and Lys10), and N-terminal acylation with specific groups (Nle, Dap, Dab) creates localized structural features that enhance MC4-R binding while reducing cross-reactivity with other melanocortin receptor subtypes.
Solution Approach 2:
The invention segments the peptide structure into distinct functional regions: the N-terminal acyl group for initial receptor interaction, the cyclic core structure for stable binding, and specific side chain configurations for selectivity. This segmentation allows optimization of MC4-R specificity while minimizing off-target effects on MC1-R, MC2-R, MC3-R, and MC5-R.
Data Source
AI summary
Melanocortin receptor-specific cyclic peptides of the formulawhere R1, R3, R4, R9 and R10 are as defined in the specification, compositions and formulations including the peptides of the foregoing formula, and methods of preventing, ameliorating or treating melanocortin receptor-mediated diseases, indications, conditions and syndromes.