基于细胞穿透肽的药物开发以抑制MDMX:p53和MDM2:p53相互作用。
Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions.
作者信息
Philippe Grégoire, Huang Yen-Hua, Cheneval Olivier, Lawrence Nicole, Zhang Zhen, Fairlie David P, Craik David J, de Araujo Aline Dantas, Henriques Sónia Troeira
机构信息
Institute for Molecular Bioscience, the University of Queensland, QLD, 4072, Australia.
出版信息
Biopolymers. 2016 Nov;106(6):853-863. doi: 10.1002/bip.22893.
The transcription factor p53 has a tumor suppressor role in leading damaged cells to apoptosis. Its activity is regulated/inhibited in healthy cells by the proteins MDM2 and MDMX. Overexpression of MDM2 and/or MDMX in cancer cells inactivates p53, facilitating tumor development. A 12-mer dual inhibitor peptide (pDI) was previously reported to be able to target and inhibit MDMX:p53 and MDM2:p53 interactions with nanomolar potency in vitro. With the aim of improving its cellular inhibitory activity, we produced a series of constrained pDI analogs featuring lactam staples that stabilize the bioactive helical conformation and fused them with a cell-penetrating peptide to increase cytosol delivery. We compared pDI and its analogs on their inhibitory potency, toxicity, and ability to enter cancer cells. Overall, the results show that these analogs keep their nanomolar affinity for MDM2 and MDMX and are highly active against cancer cells. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 853-863, 2016.
转录因子p53在引导受损细胞凋亡方面具有肿瘤抑制作用。在健康细胞中，其活性受到蛋白质MDM2和MDMX的调节/抑制。癌细胞中MDM2和/或MDMX的过表达会使p53失活，从而促进肿瘤发展。先前有报道称，一种12聚体双抑制剂肽（pDI）能够在体外以纳摩尔效力靶向并抑制MDMX:p53和MDM2:p53的相互作用。为了提高其细胞抑制活性，我们制备了一系列具有内酰胺钉的受限pDI类似物，这些内酰胺钉可稳定生物活性螺旋构象，并将它们与细胞穿透肽融合以增加胞质溶胶递送。我们比较了pDI及其类似物的抑制效力、毒性以及进入癌细胞的能力。总体而言，结果表明这些类似物对MDM2和MDMX保持纳摩尔亲和力，并且对癌细胞具有高活性。© 2016威利期刊公司。生物聚合物（肽科学）106: 853 - 863, 2016。
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