Speciation of Phenanthriplatin and Its Analogs in the Core of Tobacco Mosaic Virus

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 vir...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2018-03, Vol.140 (12), p.4279-4287
Main Authors: Vernekar, Amit A, Berger, Gilles, Czapar, Anna E, Veliz, Frank A, Wang, David I, Steinmetz, Nicole F, Lippard, Stephen J
Format: Article
Language:English
Subjects:
Models, Molecular
Molecular Structure
Organoplatinum Compounds - chemistry
Organoplatinum Compounds - metabolism
Phenanthridines - chemistry
Phenanthridines - metabolism
Tobacco Mosaic Virus - chemistry
Tobacco Mosaic Virus - metabolism
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.7b12697