Short PlGF‐derived peptides bind VEGFR‐1 and VEGFR‐2 in vitro and on the surface of endothelial cells

Abstract

The placental growth factor (PlGF), a member of VEGF family, plays a crucial role in pathological angiogenesis, especially ischemia, inflammation, and cancer. This activity is mediated by its selective binding to VEGF receptor 1 (VEGFR‐1), which occurs predominantly through receptor domains 2 and 3. The PlGF β‐hairpin region spanning residues Q87 to V100 is one of the key binding elements on the protein side. We have undertaken a study on the design, preparation, and functional characterization of the peptide reproducing this region and of a set of analogues where glycine 94, occurring at the corner of the hairpin in the native protein, is replaced by charged as well as hydrophobic residues. Also, some peptides with arginine 96 replaced by other residues have been studied. We find that the parent peptide weakly binds VEGFR‐1, but replacement of G94 with residues bearing H‐bond donating residues significantly improves the affinity. Replacement of R96 instead blocks the interaction between the peptide and the domain. The strongest affinity is observed with the G94H (peptide PlGF‐2) and G94W (peptide PlGF‐10) mutants, while the peptide PlGF‐8, bearing the R96G mutation, is totally inactive. The PlGF‐1 and PlGF‐2 peptides also bind the VEGFR‐2 receptors, though with a reduced affinity, and are able to interfere with the VEGF‐induced receptor signaling on endothelial cells. The peptides also bind VEGFR‐2 on the surface of cells, while PlGF‐8 is inactive. Data suggest that these peptides have potential applications as PlGF/VEGF mimic in various experimental settings.

Cd248a and Cd248b in zebrafish participate in innate immune responses

“…In this pathway, HIF1A acts as a central link and transmits signals to the downstream PIGF ( 36 – 39 ). PIGF (placental growth factor), is a member of the VEGF family, which can bind VEGFR1 with high affinity, plays a key role in pathological angiogenesis, especially in cancer, cardiovascular, autoimmune and inflammatory diseases ( 40 , 41 ). Thus, we examined the expression of VEGF signals upon cd248a overexpression, as expected, overexpression of cd248a increased the expression of hif1a and also upregulated the expression of pigf and vegfr1 ( Figure 9B ).…”

Structure-Based Design of Peptides Targeting VEGF/VEGFRs

“…Functional characterization of peptide HPLC in ECs showed that it presents antiangiogenic activity, being able to inhibit VEGF intracellular pathways, VEGF prosurvival activity and cell proliferation [ 34 ]. Successively, several peptides reproducing the PlGF region 87–100 and presenting a mutation in position 94 (replacing a Gly with charged residues) were tested for their ability to bind VEGFR-1 [ 66 ]. The substitution of Gly94 with His improved receptor binding affinity by approximately 1 order of magnitude.…”

Characterization of Biological Material Adsorption to the Surface of Nanoparticles without a Prior Separation Step: a Case Study of Glioblastoma-Targeting Peptide and Lipid Nanocapsules

“…A neutral LNC surface (without either SChol or DDAB) led to partial adsorption of the NFL peptide to the surface of the LNCs of approximately 45%. Concerning biological materials, especially peptides, H-bonds are largely reported in the literature to be involved in their interaction with substrates (37,38), as well as with synthetic materials, such as adsorption to the surface of nanoparticles (39,40). Thus, the interaction between NFL and the sorbitan functions of Span at the surface of LNCs through H-bonds is not surprising.…”