Structure-Based Design of Peptides against G3BP with Cytotoxicity on Tumor Cells
Structure-Based Design of Peptides against G3BP with Cytotoxicity on Tumor Cells
复制标题
基于结构的抗 G3BP 肽对肿瘤细胞具有细胞毒性的设计
DOI：
10.1021/ci900404p
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Ji, Mingjuan
中科院分区：
文献类型：
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作者：
Cui, Wei;Wei, Zhuo;Ji, Mingjuan
在此，我们报告了分子建模技术的成功应用，设计了两种对肿瘤细胞具有细胞毒性的新型肽。首先，通过精心设计的方案研究了G3BP的核运输因子2（NTF2）样结构域和RasGAP的SH3结构域之间的相互作用，该方案将同源建模、蛋白质/蛋白质对接、分子动力学模拟、分子力学/广义出生表面积（MM/GBSA）自由能计算和MM/GBSA自由能分解分析结合在一起。然后，根据理论预测，设计并合成了两种新的肽用于生物测定，它们对顺铂表现出明显的增敏作用。此外，设计的肽对正常细胞没有显着影响，而顺铂却有。我们的研究结果表明，利用这些肽来增强临床药物的疗效并选择性地杀死癌细胞是可行的。我们相信我们的工作对于寻找新的癌症疗法非常有用。
Herein, we report a successful application of molecular modeling techniques to design two novel peptides with cytotoxicity on tumor cells. First, the interactions between the nuclear transport factor 2 (NTF2)-like domain of G3BP and the SH3 domain of RasGAP were studied by a well-designed protocol, which combines homology modeling, protein/protein docking, molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and MM/GBSA free energy decomposition analysis together. Then, based on the theoretical predictions, two novel peptides were designed and synthesized for biological assays, and they showed an obvious sensitizing effect on cis-platin. Furthermore, the designed peptides had no significant effects on normal cells, while cis-platin did. Our results demonstrate that it is feasible to use the peptides to enhance the efficacy of clinical drugs and to kill cancer cells selectively. We believe that our work should be very useful for finding new therapies for cancers.