Peptide C-Terminal Modification for VEGFR-1 Inhibition
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Solution Overview
Problem
Existing synthetic peptides for inhibiting VEGFR-1 interactions with VEGF-A and PIGF ligands are not efficient at low concentrations and lack effectiveness when administered orally, limiting their therapeutic potential for angiogenesis-related pathologies.
Innovation Solution
Modifying the C-terminal of a tetrameric peptide with an amino acid having a steric hindrance comparable to a thiol or thioether group, such as R-Glu-S-Cys(Bzl)-S-Cha, enhances the peptide's ability to inhibit VEGFR-1 interactions with VEGF-A and PIGF, achieving a 50% inhibition at concentrations below 1000 nM, and maintains therapeutic efficacy when administered orally.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the original tetrameric peptide (iVR1) is used, then it can bind VEGFR-1 and inhibit VEGF-A/PIGF interaction, but the inhibitory concentration (IC50) is around 10 μM which is not efficient enough
Solution Approach 1:
The patent modifies the C-terminal of the peptide by introducing a chemical group with steric hindrance (Cys(Bzl) or Cha amino acid residue), which changes the peptide's binding parameters to achieve higher affinity for VEGFR-1, reducing the IC50 from 10 μM to below 1000 nM
2Reliability
If the original peptide is administered orally, then it can inhibit choroidal neovascularization, but the therapeutic efficacy is limited compared to intravitreal administration
Solution Approach 1:
The peptide modification at the C-terminal with steric hindrance groups improves the peptide's pharmacokinetic properties, enabling effective oral bioavailability and maintaining therapeutic efficacy when administered orally, thus eliminating the need for invasive intravitreal injections
3Ease of manufacture
If synthetic compounds are used instead of monoclonal antibodies, then production cost and complexity are reduced, but binding affinity and specificity may be compromised
Solution Approach 1:
The patent optimizes the peptide sequence and structure (introducing steric hindrance at C-terminal) to achieve binding affinity comparable to monoclonal antibodies while maintaining the advantages of synthetic production - lower cost, simpler manufacturing, and improved stability
Solution Approach 2:
The peptide combines multiple functional features: VEGFR-1 binding capability, steric hindrance for enhanced affinity, and oral bioavailability properties, creating a multi-functional synthetic compound that bridges the gap between simplicity and effectiveness
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 modified peptide, iVR1-Cys, demonstrates a 10-fold improvement in inhibitory capacity and achieves significant inhibition of choroidal neovascularization, both intravitreally and orally, compared to the unmodified peptide, iVR1.
Implementation Method 1
capable of binding VEGFR-1 and able to interfere in the interaction between the VEGF-A, PIGF, VEGF-B ligands and VEGF-A/PIGF heterodimer with VEGFR-1
Implementation Method 2
capacity to compete, in a dose-dependent manner, with VEGF-A and/or PIGF in binding with VEGFR-1
Implementation Method 3
has shown anti-angiogenic activity in vitro, interfering with the pro-angiogenic activity of PIGF and VEGF-A
Implementation Method 4
when administered orally, or by gavage, both the peptide described in Ponticelli et al. and the peptides of the present invention have demonstrated a significant capacity to inhibit choroidal neovascularization
Data Source
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AI summary
The present invention relates to peptides, a composition comprising said peptides and the use thereof as inhibitors of angiogenesis and/or neoangiogenesis. Furthermore, the present invention relates to the use of said peptides and said composition for the treatment of pathologies correlated with an incorrect angiogenesis and/or neoangiogenesis. In particular, in this context reference is made to angiogenesis and/or neoangiogenesis correlated with VEGFR1.