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首页> 外文期刊>Cellular Physiology and Biochemistry >Discovery and Characterization of a High-Affinity Small Peptide Ligand, H1, Targeting FGFR2IIIc for Skin Wound Healing
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Discovery and Characterization of a High-Affinity Small Peptide Ligand, H1, Targeting FGFR2IIIc for Skin Wound Healing

机译：高亲和力的小肽配体，H1，针对皮肤伤口愈合的靶向FGFR2IIIc的发现和表征

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Background/Aims How to aid recovery from severe skin injuries, such as burns, chronic or radiation ulcers, and trauma, is a critical clinical problem. Current treatment methods remain limited, and the discovery of ideal wound-healing therapeutics has been a focus of research. Functional recombinant proteins such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) have been developed for skin repair, however, some disadvantages in their use remain. This study reports the discovery of a novel small peptide targeting fibroblast growth factor receptor 2 IIIc (FGFR2IIIc) as a potential candidate for skin wound healing. Methods A phage-displayed peptide library was used for biopanning FGFR2IIIc-targeting small peptides. The selected small peptides binding to FGFR2IIIc were qualitatively evaluated by an enzyme-linked immunosorbent assay. Their biological function was detected by a cell proliferation assay. Among them, an optimized small peptide named H1 was selected for further study. The affinity of the H1 peptide and FGFR2IIIc was determined by an isothermal titration calorimetry device. The ability of theH1 peptide to promote skin wound repair was investigated using an endothelial cell tube formation assay and wound healing scratch assay in vitro. Subsequently, the H1 peptide was assessed using a rat skin full-thickness wound model and chorioallantoic membrane (CAM) assays in vivo. To explore its molecular mechanisms, RNA-Seq, quantitative real-time PCR, and western blot assays were performed. Computer molecular simulations were also conducted to analyze the binding model. Results We identified a novel FGFR2IIIc-targeting small peptide, called H1, with 7 amino acid residues using phage display. H1 had high binding affinity with FGFR2IIIc. The H1 peptide promoted the proliferation and motility of fibroblasts and vascular endothelial cells in vitro. In addition, the H1 peptide enhanced angiogenesis in the chick chorioallantoic membrane and accelerated wound healing in a rat full-thickness wound model in vivo. The H1 peptide activated both the PI3K-AKT and MAPK-ERK1/2 pathways and simultaneously increased the secretion of vascular endothelial growth factor. Computer analysis demonstrated that the model of H1 peptide binding to FGFR2IIIc was similar to that of FGF2 and FGFR2IIIc. Conclusion The H1 peptide has a high affinity for FGFR2IIIc and shows potential as a wound healing agent. As a substitute for bFGF, it could be developed into a novel therapeutic candidate for skin wound repair in the future.
机译：背景/目的如何帮助从严重的皮肤损伤（例如烧伤，慢性或放射性溃疡和创伤）中恢复是一个关键的临床问题。当前的治疗方法仍然有限，并且理想的伤口愈合疗法的发现一直是研究的重点。已经开发了功能性重组蛋白，例如碱性成纤维细胞生长因子（bFGF）和表皮生长因子（EGF）用于皮肤修复，但是，在使用中仍然存在一些缺点。这项研究报告发现了一种靶向成纤维细胞生长因子受体2 IIIc（FGFR2IIIc）的新型小肽，可作为皮肤伤口愈合的潜在候选物。方法使用噬菌体展示肽库对FGFR2IIIc靶向小肽进行生物淘选。通过酶联免疫吸附测定法定性地评价与FGFR2IIIc结合的所选小肽。通过细胞增殖测定法检测它们的生物学功能。其中，选择了优化的名为H1的小肽进行进一步研究。 H1肽和FGFR2IIIc的亲和力通过等温滴定热分析仪测定。使用内皮细胞管形成测定法和体外伤口愈合刮痕测定法研究了H1肽促进皮肤伤口修复的能力。随后，在体内使用大鼠皮肤全层伤口模型和绒膜尿囊膜（CAM）分析评估了H1肽。为了探索其分子机制，进行了RNA-Seq，定量实时PCR和western blot分析。还进行了计算机分子模拟以分析结合模型。结果我们通过噬菌体展示鉴定出了一种靶向FGFR2IIIc的新型小肽，称为H1，具有7个氨基酸残基。 H1与FGFR2IIIc具有高结合亲和力。 H1肽在体外促进成纤维细胞和血管内皮细胞的增殖和运动。此外，H1肽增强了鸡绒膜尿囊膜中的血管生成，并在大鼠体内全厚度伤口模型中加速了伤口愈合。 H1肽激活PI3K-AKT和MAPK-ERK1 / 2通路，并同时增加血管内皮生长因子的分泌。计算机分析表明，H1肽与FGFR2IIIc结合的模型与FGF2和FGFR2IIIc相似。结论H1肽对FGFR2IIIc具有高亲和力，并显示出作为伤口愈合剂的潜力。作为bFGF的替代品，将来它可以发展成为皮肤伤口修复的新型治疗候选物。

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