Speciation of Phenanthriplatin and Its Analogs in the Core of Tobacco Mosaic Virus,Journal of the American Chemical Society

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Speciation of Phenanthriplatin and Its Analogs in the Core of Tobacco Mosaic Virus
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-03-19 , DOI: 10.1021/jacs.7b12697
Amit A Vernekar ₁ , Gilles Berger ₁ , Anna E Czapar , Frank A Veliz , David I Wang ₁ , Nicole F Steinmetz , Stephen J Lippard ₁

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Efficient loading of drugs in novel delivery agents has the potential to substantially improve therapy by targeting the diseased tissue while avoiding unwanted side effects. Here we report the first systematic study of the loading mechanism of phenanthriplatin and its analogs into tobacco mosaic virus (TMV), previously used by our group as an efficient carrier for anticancer drug delivery. A detailed investigation of the preferential uptake of phenanthriplatin in its aquated form (∼2000 molecules per TMV particle versus ∼1000 for the chlorido form) is provided. Whereas the net charge of phenanthriplatin analogs and their ionic mobilities have no effect on loading, the reactivity of aqua phenanthriplatin with the glutamates, lining the interior walls of the channel of TMV, has a pronounced effect on its loading. MALDI-MS analysis along with NMR spectroscopic studies of a model reaction of hydroxy-phenanthriplatin with acetate establish the formation of stable covalent adducts. The increased number of heteroaromatic rings on the platinum ligand appears to enhance loading, possibly by stabilizing hydrophobic stacking interactions with TMV core components, specifically Pro102 and Thr103 residues neighboring Glu97 and Glu106 in the channel. Electron transfer dissociation MS/MS fragmentation, a technique that can prevent mass-condition-vulnerable modification of proteins, reveals that Glu97 preferentially participates over Glu106 in covalent bond formation to the platinum center.

中文翻译：

烟草花叶病毒核心菲铂及其类似物的形态分析

在新型递送剂中有效装载药物有可能通过靶向患病组织来显着改善治疗，同时避免不必要的副作用。在此，我们报告了菲铂及其类似物在烟草花叶病毒（TMV）中的负载机制的首次系统研究，该病毒此前被我们小组用作抗癌药物递送的有效载体。提供了对水合形式菲铂优先吸收的详细研究（每个 TMV 颗粒约 2000 个分子，而氯化形式为约 1000 个分子）。虽然菲铂类似物的净电荷及其离子迁移率对其负载没有影响，但水菲铂与排列在TMV通道内壁上的谷氨酸的反应性对其负载有显着影响。 MALDI-MS 分析以及羟基菲铂与乙酸盐模型反应的 NMR 光谱研究确定了稳定共价加合物的形成。铂配体上杂芳环数量的增加似乎增强了负载，可能是通过稳定与 TMV 核心成分的疏水堆积相互作用，特别是通道中邻近 Glu97 和 Glu106 的 Pro102 和 Thr103 残基。电子转移解离 MS/MS 碎片是一种可以防止蛋白质质量条件脆弱修饰的技术，表明 Glu97 比 Glu106 优先参与与铂中心的共价键形成。

更新日期：2018-03-19

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