修饰的基于RGD的肽的合成及其体外活性。,ChemMedChem

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修饰的基于RGD的肽的合成及其体外活性。
ChemMedChem ( IF 3.6 ) Pub Date : 2019-01-09 , DOI: 10.1002/cmdc.201800704
Fatima Hamdan ₁ , Zahra Bigdeli ₁ , S Mohsen Asghari ₂ , Afsaneh Sadremomtaz ₂ , Saeed Balalaie _{1,

3}

Affiliation

Arg-Gly-Asp（RGD）肽代表与细胞粘附相关的最杰出的识别基序，该基序与已经针对癌症治疗的αvβ3整联蛋白结合。已经设计并合成了各种含RGD的肽和拟肽，以选择性抑制该整联蛋白。在这项研究中，通过使用固相肽合成技术，通过在RGD的C和N末端掺入短生物活性肽Phe-Ala-Lys-Leu-Phe（FAKLF），可以合成基于RGD的肽。方法。通过制备型RP-HPLC纯化所述肽，并通过HRMS（ESI）确认其结构。MTT分析显示，RGD和FAKLF肽以剂量依赖性方式抑制人脐静脉内皮细胞（HUVEC）的增殖，IC50值分别为3000和500 ng mL-1，分别。有趣的是，观察到FAKLFRGD和RGDFAKLF肽组合结构的抗增殖活性得到了极大的改善，分别导致IC50值为200和136.7 ng mL-1。同时，基于凋亡结果，根据其抗增殖活性，肽诱导凋亡的潜力表明RGD和FAKLF肽，以及根据其组合合成的肽以剂量依赖的方式诱导细胞凋亡，然后被抑制。内皮细胞的增殖。此外，d-亮氨酸的掺入增加了这些肽对细胞凋亡的诱导。导致IC50值分别为200和136.7 ng mL-1。同时，基于凋亡结果，根据其抗增殖活性，肽诱导凋亡的潜力表明RGD和FAKLF肽以及基于它们的组合合成的肽以剂量依赖的方式诱导细胞凋亡，随后被抑制。内皮细胞的增殖。此外，d-亮氨酸的掺入增加了这些肽对细胞凋亡的诱导。导致IC50值分别为200和136.7 ng mL-1。同时，基于凋亡结果，根据其抗增殖活性，肽诱导凋亡的潜力表明RGD和FAKLF肽以及基于它们的组合合成的肽以剂量依赖的方式诱导细胞凋亡，随后被抑制。内皮细胞的增殖。此外，d-亮氨酸的掺入增加了这些肽对细胞凋亡的诱导。并且基于它们的组合合成的肽以剂量依赖的方式诱导细胞凋亡，随后抑制内皮细胞的增殖。此外，d-亮氨酸的掺入增加了这些肽对细胞凋亡的诱导。并且基于它们的组合合成的肽以剂量依赖的方式诱导细胞凋亡，随后抑制内皮细胞的增殖。此外，d-亮氨酸的掺入增加了这些肽对细胞凋亡的诱导。

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Synthesis of Modified RGD-Based Peptides and Their in vitro Activity.

Arg-Gly-Asp (RGD) peptides represent the most outstanding recognition motif involved in cell adhesion that binds to the αv β3 integrin, which has been targeted for cancer therapy. Various RGD-containing peptides and peptidomimetics have been designed and synthesized to selectively inhibit this integrin. In this study, the synthesis of RGD-based peptides through the incorporation of the short bioactive peptide Phe-Ala-Lys-Leu-Phe (FAKLF) at the C and N termini of RGD has been achieved by using a solid-phase peptide synthesis approach. The peptides were purified by means of preparative RP-HPLC and their structures were confirmed through HRMS (ESI). The MTT assay revealed that the RGD and FAKLF peptides inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, with IC50 values of 3000 and 500 ng mL-1 , respectively. Interestingly, a drastic improvement was observed in the antiproliferative activity of the combined structures of the FAKLFRGD and RGDFAKLF peptides, leading to IC50 values of 200 and 136.7 ng mL-1 , respectively. Meanwhile, based on apoptosis results, the potential of peptides to induce apoptosis, in accordance with their antiproliferative activity, indicated that the RGD and FAKLF peptides, and the peptides synthesized based on their combinations induced cell apoptosis in a dose-dependent manner followed by inhibition of the proliferation of endothelial cells. Moreover, the incorporation of d-leucine increased the induction of apoptosis by these peptides.

更新日期：2019-01-09

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