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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Engineered conformation-dependent VEGF peptide mimics are effective in inhibiting VEGF signaling pathways
Daniele Vicari1, Kevin C Foy, Eric M Liotta
1Department of Microbiology, Ohio State University, Columbus, Ohio 43210, USA.
Abstract:
Angiogenesis, or formation of new blood vessels, is crucial to cancer tumor growth. Tumor growth, progression, and metastasis are critically influenced by the production of the pro-angiogenic vascular endothelial growth factor (VEGF). Promising anti-angiogenic drugs are currently available; however, their susceptibilities to drug resistance and long term toxicity are serious impediments to their use, thus requiring the development of new therapeutic approaches for safe and effective angiogenic inhibitors. In this work, peptides were designed to mimic the VEGF-binding site to its receptor VEGFR-2. The VEGF conformational peptide mimic, VEGF-P3(CYC), included two artificial cysteine residues, which upon cyclization constrained the peptide in a loop native-like conformation to better mimic the anti-parallel structure of VEGF. The engineered cyclic VEGF mimic peptide demonstrated the highest affinity to VEGFR-2 by surface plasmon resonance assay. The VEGF peptide mimics were evaluated as inhibitors in several in vitro assays in which VEGF-dependent signaling pathways were observed. All VEGF mimics inhibited VEGFR-2 phosphorylation with VEGF-P3(CYC) showing the highest inhibitory effects when compared with unstructured peptides. Additionally, we show in several angiogenic in vitro assays that all the VEGF mimics inhibited endothelial cell proliferation, migration, and network formation with the conformational VEGF-P3 (CYC) being the best. The VEGF-P3(CYC) also caused a significant delay in tumor development in a transgenic model of VEGF(+/-)Neu2-5(+/-). These results indicate that the structure-based design is important for the development of this peptidomimetic and for its anti-angiogenic effects.
Insights
Researchers designed a novel cyclic peptide, VEGF-P3(CYC), that effectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2) signaling. This peptide mimic shows promise as a safe and effective anti-angiogenic therapy for cancer by blocking tumor blood vessel formation.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Angiogenesis, the formation of new blood vessels, is vital for tumor growth, progression, and metastasis.
- Vascular endothelial growth factor (VEGF) drives angiogenesis, making it a key therapeutic target.
- Existing anti-angiogenic drugs face challenges with drug resistance and toxicity, necessitating novel therapeutic strategies.
Purpose of the Study:
- To design and develop novel peptide mimics that inhibit the interaction between VEGF and its receptor VEGFR-2.
- To create a structure-based peptidomimetic with improved affinity and inhibitory effects against VEGFR-2.
- To evaluate the anti-angiogenic potential of these peptide mimics in vitro and in vivo.
Main Methods:
- Peptides were engineered to mimic the VEGF-binding site of VEGFR-2, incorporating artificial cysteine residues for cyclization.
- Surface plasmon resonance (SPR) was used to assess the binding affinity of peptide mimics to VEGFR-2.
- In vitro assays evaluated the inhibition of VEGFR-2 phosphorylation, endothelial cell proliferation, migration, and network formation.
- In vivo studies utilized a transgenic mouse model to assess the impact on tumor development.
Main Results:
- The cyclic peptide mimic, VEGF-P3(CYC), demonstrated the highest affinity for VEGFR-2 compared to unstructured mimics.
- VEGF-P3(CYC) exhibited superior inhibition of VEGFR-2 phosphorylation and downstream signaling pathways.
- All designed VEGF mimics effectively inhibited endothelial cell proliferation, migration, and network formation, with VEGF-P3(CYC) being the most potent.
- VEGF-P3(CYC) significantly delayed tumor development in a transgenic mouse model.
Conclusions:
- Structure-based design is crucial for developing effective peptidomimetics with anti-angiogenic properties.
- The cyclic peptide VEGF-P3(CYC) represents a promising candidate for a new generation of safe and effective anti-angiogenic therapies.
- Targeting the VEGF-VEGFR-2 interaction with engineered peptide mimics offers a viable strategy for cancer treatment.
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