Abstract
Vascular endothelial growth factor (VEGF), one of the most important angiogenic factors, plays an essential role in both physiological and pathological angiogenesis through binding to VEGF receptors (VEGFRs). Here we report a novel peptide designated HRHTKQRHTALH (peptide HRH), which was isolated from the Ph.D. -12 phage display library using VEGFR-Fc fusion protein as the bait. This peptide was found to dose-dependently inhibit the proliferation of human umbilical vein endothelial cells stimulated by VEGF. The anti-angiogenesis effect of the HRH peptide was further confirmed in vivo using the chick chorioallantoic membrane assay, which was also dose-dependent. Besides, peptide HRH was proved to inhibit corneal neovascularization in an alkali-burnt rat corneal model and a suture-induced rat corneal model. Taken together, these findings suggest that the HRH peptide can inhibit angiogenesis both in vitro and in vivo. Consequently, the HRHTKQRHTALH peptide might be a promising lead peptide for the development of potential angiogenic inhibitors.
Highlights
The deregulated and persistent angiogenesis is a critical hallmark of neovascular or exudative age-related macular degeneration (AMD).[1]
Vascular endothelial growth factor (VEGF) is a pivotal angiogenic factor, which signals through its receptors on the cell surface to manipulate multiple facets of angiogenesis.[5]
The results revealed that selected clones displaying HRHTKQRHTALH, YITPYAHLRGGN and SVSVGMKPSPRP had greater reactivity for VEGF receptors (VEGFRs)-Fc fusion protein compared with other phage clones (Figure 1)
Summary
The deregulated and persistent angiogenesis is a critical hallmark of neovascular or exudative age-related macular degeneration (AMD).[1]. Most angiogenic inhibitors in clinical use are proteins, and a few are small molecules.[6] Small-molecule therapeutics may sustain reduced target selectivity because of their fairly small size, whereas protein drugs are inclined to have high target specificity owning to more interactions between them, this comes at the expense of poor membrane permeability, metabolic instability and low bioavailability.[17] peptide agents have the advantages of both small molecules (low cost, oral bioavailability, membrane permeability, metabolic stability and conformational restriction) and proteins (target specificity and high potency). An identified peptide with the sequence HRHTKQRHTALH was synthesized, and its antiangiogenesis abilities were evaluated and confirmed in vitro and in vivo. This peptide holds great promise as an angiogenic inhibitor for the treatment of ophthalmic diseases caused by excessive angiogenesis
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