Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, Barcelona, 08028, Spain.
Department of Inorganic and Organic Chemistry, University of Barcelona, Martí I Franqués 1-11, Barcelona, 08028, Spain.
Chembiochem. 2019 Aug 16;20(16):2079-2084. doi: 10.1002/cbic.201900355. Epub 2019 Jul 22.
The epidermal growth factor (EGF) pathway, being overactive in a number of cancers, is a good target for clinical therapy. Although several drugs targeting the EGF receptor (EGFR) are on the market, tumours acquire resistance very rapidly. As an alternative, small molecules and peptides targeting EGF have been developed, although with moderate success. Herein, we report the use of mirror-image phage display technology to discover protease-resistant peptides with the capacity to inhibit the EGF-EGFR interaction. After the chemical synthesis of the enantiomeric protein d-EGF, two phage-display peptide libraries were used to select binding sequences. The d versions of these peptides bound to natural EGF, as confirmed by surface acoustic waves (SAWs). High-field NMR spectroscopy showed that the best EGF binder, d-PI_4, interacts preferentially with an EGF region that partially overlaps with the receptor binding interface. Importantly, we also show that d-PI_4 efficiently disrupts the EGF-EGFR interaction. This methodology represents a straightforward approach to find new protease-resistant peptides with potential applications in cancer therapy.
表皮生长因子（EGF）通路在多种癌症中过度活跃，是临床治疗的一个很好的靶点。尽管有几种针对表皮生长因子受体（EGFR）的药物已经上市，但肿瘤很快就会产生耐药性。作为替代方法，已经开发出针对 EGF 的小分子和肽类药物，但效果中等。在此，我们报告使用镜像噬菌体展示技术来发现具有抑制 EGF-EGFR 相互作用能力的抗蛋白酶肽。在化学合成对映体蛋白 d-EGF 后，使用两个噬菌体展示肽文库来选择结合序列。这些肽的 d 版本与天然 EGF 结合，这一点通过表面声波（SAW）得到了证实。高场 NMR 光谱表明，最佳的 EGF 结合物 d-PI_4 优先与与受体结合界面部分重叠的 EGF 区域相互作用。重要的是，我们还表明 d-PI_4 可有效破坏 EGF-EGFR 相互作用。这种方法代表了一种直接的方法，可以找到具有潜在癌症治疗应用的新型抗蛋白酶肽。
