David H Koch Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5112-7. doi: 10.1073/pnas.0915141107. Epub 2010 Feb 26.
Inhibition of blood vessel formation is a viable therapeutic approach in angiogenesis-dependent diseases. We previously used a combinatorial screening on vascular endothelial growth factor (VEGF)-activated endothelial cells to select the sequence CPQPRPLC and showed that the motif Arg-Pro-Leu targets VEGF receptor-1 and neuropilin-1. Here, we evaluated and validated (D)(LPR), a derivative molecule with strong antiangiogenesis attributes. This prototype drug markedly inhibits neovascularization in three mouse models: Matrigel-based assay, functional human/murine blood vessel formation, and retinopathy of prematurity. In addition to its systemic activity, (D)(LPR) also inhibits retinal angiogenesis when administered in an eye-drop formulation. Finally, in preliminary studies, we have showed targeted drug activity in an experimental tumor-bearing mouse model. These results show that drugs targeting extracellular domains of VEGF receptors are active, affect signal transduction, and have potential for clinical application. On a larger context, this study illustrates the power of ligand-directed selection plus retro-inversion for rapid drug discovery and development.
抑制血管生成是血管生成依赖性疾病的一种可行的治疗方法。我们之前使用血管内皮生长因子(VEGF)激活的内皮细胞的组合筛选来选择序列 CPQPRPLC，并表明该基序 Arg-Pro-Leu 靶向 VEGF 受体-1 和神经纤毛蛋白-1。在这里，我们评估和验证了具有强大抗血管生成特性的衍生分子(D)(LPR)。这种原型药物在三种小鼠模型中显著抑制新血管生成：基于 Matrigel 的测定、功能性人/鼠血管生成和早产儿视网膜病变。除了其全身活性外，(D)(LPR)在滴眼剂配方中给药时还抑制视网膜血管生成。最后，在初步研究中，我们在实验性荷瘤小鼠模型中显示了靶向药物活性。这些结果表明，靶向 VEGF 受体细胞外结构域的药物具有活性，可影响信号转导，具有临床应用的潜力。从更大的角度来看，这项研究说明了配体定向选择加反向反转在快速药物发现和开发中的强大作用。
