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Discovery of pan-VEGF inhibitory peptides directed to the extracellular ligand-binding domains of the VEGF receptors

机译：发现针对VEGF受体胞外配体结合域的pan-VEGF抑制肽

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Receptor tyrosine kinases (RTKs) are key molecules in numerous cellular processes, the inhibitors of which play an important role in the clinic. Among them are the vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR), which are essential in the formation of new blood vessels by angiogenesis. Anti-VEGF therapy has already shown promising results in oncology and ophthalmology, but one of the challenges in the field is the design of specific small-molecule inhibitors for these receptors. We show the identification and characterization of small 6-mer peptides that target the extracellular ligand-binding domain of all three VEGF receptors. These peptides specifically prevent the binding of VEGF family members to all three receptors and downstream signaling but do not affect other angiogenic RTKs and their ligands. One of the selected peptides was also very effective at preventing pathological angiogenesis in a mouse model of retinopathy, normalizing the vasculature to levels similar to those of a normal developing retina. Collectively, our results suggest that these peptides are pan-VEGF inhibitors directed at a common binding pocket shared by all three VEGFRs. These peptides and the druggable binding site they target might be important for the development of novel and selective small-molecule, extracellular ligand-binding inhibitors of RTKs (eTKIs) for angiogenic-dependent diseases.
机译：受体酪氨酸激酶（RTK）是许多细胞过程中的关键分子，其抑制剂在临床中起着重要作用。其中包括血管内皮生长因子（VEGF）家族成员及其受体（VEGFR），它们在通过血管生成形成新血管中必不可少。抗VEGF疗法已经在肿瘤学和眼科领域显示出令人鼓舞的结果，但是该领域的挑战之一是针对这些受体的特异性小分子抑制剂的设计。我们显示了针对所有三个VEGF受体的细胞外配体结合域的小型6-mer肽的鉴定和表征。这些肽可特异性阻止VEGF家族成员与所有三个受体的结合和下游信号传导，但不影响其他血管生成RTK及其配体。所选择的肽之一在预防视网膜病变的小鼠模型中的病理性血管生成方面也非常有效，可将脉管系统正常化至与正常发育的视网膜相似的水平。总体而言，我们的结果表明，这些肽是针对所有三种VEGFR共有的共同结合口袋的pan-VEGF抑制剂。这些肽和它们靶向的可药物结合位点可能对于开发新型的和选择性的小分子，RTKs（eTKIs）的血管外依赖性疾病的细胞外配体结合抑制剂很重要。

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