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.
Highlights
Blocking agents aimed at better understanding the angiogenic mechanism and development of potential inhibitors [13,14,15]
Zilberberg et al [58] identified that the sequence 79 –93 of vascular endothelial growth factor (VEGF) is involved in the interaction with VEGF receptor-2
The VEGF residues critical for antibody binding are distinct from those important for high affinity receptor binding, they occupy a common region on VEGF demonstrating that the neutralizing effect of antibody binding results from steric blocking of VEGF-receptor interactions
Summary
Blocking agents aimed at better understanding the angiogenic mechanism and development of potential inhibitors [13,14,15]. Peptidomimetics is the approach of reproducing the biological activity or binding properties in a smaller molecule, like peptides or modified peptides that were designed to mimic the desired region. This approach demonstrated successful results in studies with. Peptides are excellent candidates for drug design because they demonstrate better target specificity and less susceptibility to drug resistance than small molecules. Peptides demonstrate several advantages like lower developing and manufacturing costs, improved organ or tumor penetration, and higher activity per mass when compared with antibodies or large proteins [47, 48]. The main goal of this work was to create molecules that would retain the structural similarity with the binding site region and demonstrate bioactivity “in vivo.”
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