Using the MCoTI-II Cyclotide Scaffold To Design a Stable Cyclic Peptide Antagonist of SET, a Protein Overexpressed in Human Cancer
Using the MCoTI-II Cyclotide Scaffold To Design a Stable Cyclic Peptide Antagonist of SET, a Protein Overexpressed in Human Cancer
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DOI：
10.1021/acs.biochem.5b00529
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发表时间：
2016-01-19
期刊：
影响因子：
2.9
通讯作者：
Craik, David J.
中科院分区：
文献类型：
--
作者：
D'Souza, Charlotte;Henriques, Sonia Troeira;Craik, David J.
由于SET蛋白能够抑制肿瘤抑制基因蛋白磷酸酶2A(PP2A)的功能，因此有望成为肿瘤治疗的药物靶点。来源于载脂蛋白E(ApoE)的COG多肽是SET的强效拮抗剂，它们与细胞内SET结合后对癌细胞产生细胞毒作用，并调节核因子-kappaB(NF-kappa B)信号通路。然而，由于COG多肽对蛋白质的降解稳定性差，生物利用度低，其治疗潜力有限。在本研究中，COG多肽COG1410通过将其嫁接到超稳定环肽支架Momordica cochinensis Trypsin Inhibitor-II(MCoTI-II)上得到稳定。接枝的MCoTI-II多肽对癌细胞株具有细胞毒作用，在人血清中表现出高度的稳定性。最有效的MCoTI-II多肽可抑制脂多糖(LPS)介导的小鼠巨噬细胞中核因子-kappaB的激活。总体而言，这项研究证明了MCoTI-II支架在开发稳定的多肽药物用于癌症治疗方面的应用。
The SET protein is a promising drug target in cancer therapy, because of its ability to inhibit the function of the tumor suppressor gene protein phosphatase 2A (PP2A). COG peptides, derived from apolipoprotein E (apoE), are potent antagonists of SET; they induce cytotoxicity in cancer cells upon binding to intracellular SET and modulate the nuclear factor kappa B (NF-kappa B) signaling pathway. However, the therapeutic potential of COG peptides is limited, because of their poor proteolytic stability and low bioavailability. In this study, the COG peptide, COG1410, was stabilized by grafting it onto the ultrastable cyclic peptide scaffold, Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The grafted MCoTI-II peptides were cytotoxic to a cancer cell line and showed high stability in human serum. The most potent grafted MCoTI-II peptide inhibited lipopolysaccharide (LPS)-mediated activation of NF-kappa B in murine macrophages. Overall, this study demonstrates the application of the MCoTI-II scaffold for the development of stable peptide drugs for cancer therapy.