Multi-target Peptides for Opioid Analgesia
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Solution Overview
Problem
Current opioid analgesics, such as morphine and fentanyl, are effective for severe pain but come with significant side effects like tolerance, addiction, constipation, and respiratory depression, limiting their clinical application, and existing multi-target opioid molecules do not provide ideal analgesic effects and potency.
Innovation Solution
Development of multi-target polypeptides that simultaneously activate opioid and neuropeptide FF receptors through amino acid substitution in the chimeric peptide BN-9, specifically compounds 1-9 with varying amino acid sequences, to enhance analgesic efficacy and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional opioid analgesics (morphine, fentanyl) are used to treat severe pain, then analgesic efficacy is improved, but serious adverse reactions (tolerance, addiction, constipation, respiratory depression) occur
Solution Approach 1:
The invention segments the opioid molecule into two functional parts: an opioid agonist portion (providing analgesic effect) and a neuropeptide FF ligand portion (providing anti-tolerance and anti-addiction effects). This segmentation allows each part to independently contribute to different therapeutic goals, resolving the contradiction between efficacy and side effects
Solution Approach 2:
The invention creates a composite peptide molecule (ESP7) that combines two different bioactive sequences: the opioid agonist sequence (Tyr-Pro-Phe-Phe-Gly-Leu-Met-NH2) and the neuropeptide FF sequence. This composite structure enables simultaneous activation of multiple receptor systems, achieving both strong analgesia and reduced tolerance/addiction
2Object-generated harmful factors
If chimeric peptide BN-9 is developed to simultaneously activate opioid and NPFF receptors, then side effects (tolerance, constipation) are reduced, but analgesic effect and potency are not ideal
Solution Approach 1:
The invention modifies the parent compound BN-9 by changing specific amino acid parameters at key positions. Nine derivatives were synthesized with systematic variations in amino acid composition, and compound 9 (Tyr-D-Ala-Gly-NMe-Phe-Gly-Pro-Gln-Arg-Phe-NH2) showed optimal balance between potency and reduced side effects through these parameter optimizations
Solution Approach 2:
The invention applies local quality modification by specifically targeting certain amino acid positions in the peptide sequence for modification while leaving other positions unchanged. This selective local modification allows optimization of specific properties (analgesic potency, receptor selectivity) without compromising the overall dual-receptor activation mechanism
Data Source
AI summary
Provided are nine multi-target polypeptides of an opioid and a neuropeptide FF receptor, where an amino acid is replaced on the basis of opioid peptide biphalin- and NPFF-based chimeric peptide BN-9, and acquired are the multi-target polypeptides capable of concurrently activating various opioid and NPFF system receptors.