Peptidic TGF-beta Antagonists Resolving Aggregation
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Solution Overview
Problem
There is a need for soluble, low-molecular weight peptide antagonists of TGF-β that can inhibit TGF-β activity without aggregating in aqueous solutions, as existing peptides often aggregate, reducing their effectiveness in treating fibrosis and cancer.
Innovation Solution
Development of low-molecular weight TGF-β-binding peptides with specific amino acid sequences, such as ETWIWLDTNMG, that inhibit TGF-β signaling by attenuating gene expression and proteins involved in fibrosis and cancer, while maintaining stability and avoiding aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If low-molecular weight TGF-β-binding peptides are used to inhibit TGF-β activity, then therapeutic effectiveness is improved, but aggregation in aqueous solution occurs reducing stability
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the peptide to alter its physicochemical properties. Specifically, the peptide sequence (e.g., ETWIWLDTNMG) is designed with specific hydrophobic and hydrophilic residues to change its solubility characteristics and reduce aggregation propensity while maintaining TGF-β binding affinity. This allows the peptide to remain stable in aqueous solutions at therapeutic concentrations.
2Reliability
If peptide sequence is optimized for TGF-β binding affinity, then inhibitory activity is improved, but aggregation propensity increases
Solution Approach 1:
The patent applies local quality by creating distinct regions within the peptide sequence with different properties. The peptide contains a TGF-β binding region with specific hydrophobic residues (e.g., W, L, M, G) that provide high binding affinity, while other regions contain hydrophilic or charged residues that prevent aggregation. This spatial separation of functions allows the peptide to maintain both high inhibitory activity and low aggregation propensity simultaneously.
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 peptides effectively inhibit TGF-β activity, reducing fibrosis and cancer-related protein expressions, and demonstrate reduced aggregation propensity, enhancing their stability and therapeutic potential.
Implementation Method 1
The TGF-β-binding peptide is capable of establishing an inhibitory intermolecular interaction with TGF-β
Data Source
AI summary
The present invention provides peptidic TGF-β antagonists capable of inhibiting TGF-β signaling and disrupting the biochemical events that promote fibrosis and the epithelial-mesenchymal transition. The peptidic TGF-β antagonist may contain from 11 to 28 amino acid residues (for instance, may consist of from 12 to 16 amino acid residues) and may have the following structure (II):NH2′ETWIWLDTNMG-Xaa1-Y′COOH (II)wherein Xaa1 is any amino acid and Y is a peptide having from 0 to 9 amino acids. The peptidic TGF-β antagonists can advantageously be used for the prevention, treatment, and/or alleviation of the symptoms of a condition associated with an increase in TGF-β activity, including fibrosis (such as fibrosis of the skin, liver, lungs, and heart, among others) and cancer (including various carcinomas, such as squamous cell carcinoma, sarcomas, and metastatic cancers).