Modified Peptide Complex for TrkB Agonist Activity and Stability
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Solution Overview
Problem
Existing TrkB agonists face pharmacokinetic issues and limited progress in treating neurodegenerative and neuropsychiatric disorders, necessitating the development of novel compounds with TrkB binding and agonist activity.
Innovation Solution
A peptide complex comprising a first peptide with a specific amino acid sequence, potentially modified by substitution, deletion, addition, or insertion, and connected via a linker, exhibits TrkB binding and agonist activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If BDNF is used as a therapeutic drug for neurodegenerative and neuropsychiatric disorders, then TrkB agonist activity is achieved, but pharmacokinetic problems occur
Solution Approach 1:
The patent modifies the molecular parameters of the original BDNF ligand by creating peptide variants with altered amino acid sequences. These parameter changes in the peptide structure improve pharmacokinetic properties such as stability and half-life while preserving the essential TrkB agonist activity, thus resolving the contradiction between reliability of action and duration of action.
Solution Approach 2:
The invention creates composite peptide structures that combine elements of natural BDNF with modified amino acid sequences. These composite peptides integrate the beneficial TrkB binding activity of natural BDNF with improved pharmacokinetic characteristics introduced through structural modifications, effectively resolving the pharmacokinetic problems associated with native BDNF.
2Duration of action of moving object
If TrkB agonist antibodies and low-molecular-weight compounds are developed as alternatives to BDNF, then pharmacokinetic issues are improved, but TrkB binding affinity may be reduced
Solution Approach 1:
The patent systematically varies parameters of the peptide structure including amino acid composition, sequence length, and post-translational modifications to optimize both pharmacokinetic properties and TrkB binding affinity. This parameter optimization ensures that the peptide maintains high binding affinity while achieving improved pharmacokinetic characteristics compared to natural BDNF.
Solution Approach 2:
The invention creates peptide copies of the critical binding regions of natural BDNF that interact with TrkB. These copied sequences are optimized to maintain the essential binding interactions while improving stability and pharmacokinetic properties, thus achieving both high affinity and improved duration of action.
3Stability of the object's composition
If peptide sequences are modified to improve stability, then pharmacokinetic properties are enhanced, but binding activity may be affected
Solution Approach 1:
The patent applies local quality modifications by making targeted amino acid substitutions at specific positions in the peptide sequence that are less critical for binding. These localized changes improve overall peptide stability without disrupting the critical binding interface regions, thus enhancing pharmacokinetic properties while preserving TrkB binding activity.
Solution Approach 2:
The invention segments the peptide structure into distinct functional regions: a stable core structure that provides pharmacokinetic stability and a flexible binding region that maintains TrkB interaction. This segmentation allows independent optimization of stability and binding activity, resolving the contradiction between these two properties.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The peptide complex demonstrates strong TrkB binding affinity and agonist activity, activating signal transduction pathways similar to BDNF, offering potential therapeutic benefits for neurodegenerative and neuropsychiatric disorders.
Implementation Method 1
The peptide complex comprises a first peptide and has TrkB binding activity
Data Source
AI summary
[Problem] To provide a novel compound having TrkB-binding activity. [Solution] A peptide complex having TrkB-binding activity comprises a first peptide having an amino acid sequence represented by X1-X2-X3-X4-3Py-W-X5-X6-X7-X8-X9-X10-V-X11-C (SEQ ID NO: 1), or an amino acid sequence in which 1 to 4 amino acids have been substituted, deleted, added or inserted, wherein: X1 and X10 are amino acids having an aromatic ring in the side chain thereof; X2, X9, and X11 are any amino acids; X3 and X5 are secondary amino acids; X4 and X7 are amino acids having an aromatic ring which may be substituted in the side chain thereof; and X6 and X8 are amino acids having a chain alkyl group in the side chain thereof.