Cyclopeptide Dual Agonists for Peripheral Pain Relief
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Solution Overview
Problem
Current opioid analgesic drugs like morphine and fentanyl have significant side effects such as respiratory suppression, tolerance, abuse, and constipation, limiting their long-term clinical application, and existing peptide drugs face challenges with instability and short analgesic duration.
Innovation Solution
Development of multi-target cyclopeptide molecules for opioid receptors and neuropeptide FF receptors, specifically designed with amino acid substitutions and cyclization, which act as dual agonists, preventing central activation and reducing side effects like tolerance and constipation, with enhanced stability and prolonged analgesic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional opioid drugs (morphine, fentanyl) are used for pain treatment, then analgesic effect is achieved, but side effects (respiratory suppression, tolerance, abuse, constipation) increase
Solution Approach 1:
The invention segments the opioid receptor targeting function by designing cyclopeptide molecules that selectively bind to peripheral opioid receptors (POM, DOR, KOR) while excluding central receptors. This spatial segmentation allows analgesic effect at the peripheral level without central nervous system penetration, thereby reducing side effects like respiratory suppression and addiction
Solution Approach 2:
The cyclopeptide molecules are designed as multi-functional agents that simultaneously target multiple opioid receptor subtypes (POM, DOR, KOR) and neuropeptide FF receptors. This multi-functionality enhances analgesic efficacy through synergistic activation of multiple pathways while maintaining peripherally restricted action to minimize central side effects
2Reliability
If peptide drugs are used to improve analgesic properties, then receptor selectivity and bioavailability are enhanced, but stability decreases
Solution Approach 1:
The invention applies parameter changes by modifying the peptide structure through cyclization (changing the topological parameter from linear to cyclic) and incorporating non-natural amino acids (changing chemical composition parameters). These modifications significantly enhance stability against proteolytic degradation while preserving receptor binding affinity and selectivity
3Productivity
If multi-target agonists are developed to reduce side effects, then analgesic efficiency improves, but analgesic duration is insufficient
Solution Approach 1:
The invention creates composite molecular structures by combining cyclic peptide backbones with specific amino acid sequences that target multiple receptor types. This composite design achieves both high analgesic efficiency through multi-receptor activation and prolonged duration through enhanced metabolic stability of the cyclic structure
Data Source
AI summary
Provided is a novel peripherally restricted multi-target cyclopeptide molecule for an opioid receptor and a neuropeptide FF (NPFF) receptor, or a pharmaceutically acceptable salt thereof. By using DN-9 as a chemical template, structural optimization is performed on opioid peptide and NPFF pharrnacophores by means of polypeptide chemical strategies such as amino acid replacement and cyclization modification to obtain a series of cyclopeptide molecules. The cyclopeptide molecules can activate both opioid receptors and NPFF receptors, and the analgesic activity and the analgesic duration thereof are greatly increased compared with parent DN-9 molecules, and opioid side effects such as analgesic tolerance, constipation, and addiction are reduced.