Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

Abstract

Electrospray ionisation mass spectrometry was used to analyse the reactions of metal compounds with mixtures of selected proteins. Three representative medicinally relevant compounds, cisplatin, transplatin and the organometallic ruthenium compound RAPTA-C, were reacted with a pool of three proteins, ubiquitin, cytochrome c and superoxide dismutase, and the reaction products were analysed using high-resolution mass spectrometry. Highly informative electrospray ionisation mass spectra were acquired following careful optimisation of the experimental conditions. The formation of metal-protein adducts was clearly observed for the three proteins. In addition, valuable information was obtained on the nature of the proteinbound metallofragments, on their distribution among the three different proteins and on the binding kinetics. The platinum compounds were less reactive and considerably less selective in protein binding than RAPTA-C, which showed a high affinity towards ubiquitin and cytochrome c, but not superoxide dismutase. In addition, competition studies between cisplatin and RAPTA-C showed that the two metallodrugs have affinities for the same amino acid residues on protein binding.

A Ruthenium Antimetastasis Agent Forms Specific Histone Protein Adducts in the Nucleosome Core

“…Furthermore, mass spectrometric studies have shown highly protein-selective binding of RAPTA-C compared to cisplatin in samples containing protein mixtures, which was attributed to steric and hydrophobic effects. [29] The proclivity for site specific association at defined locations on the nucleosome core implies that histone binding could contribute to the therapeutic activity of RAPTA compounds. In fact, following RAPTA-C treatment of cancer cells, we found that approximately 5 % of the intracellular ruthenium content was associated with chromatin, which indicates that the nucleosome is a possible therapeutic target for this drug (see the Experimental Section).…”

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

“…The enzyme TrxR is attracting growing interest as a target for a variety of metallodrugs [22,27,53]. Both X-ray crystallography and MALDI-MS were used previously to show that several terpyridineplatinum(II) complexes bind to TrxR [22], while various gold complexes have also proven to be potent inhibitors of this enzyme [24][25][26].…”

A QM/MM study of the binding of RAPTA ligands to cathepsin B

“…The poor correlation between the binding to DNA and their cytotoxicity has suggested that Ru(II)-arene PTA (RAPTA) compounds act through a mechanism different from that established for classical platinum anticancer drugs. Hence, it is believed that the interaction of the RAPTA complexes with intracellular or extracellular proteins [13,20,21] may represent their primary mechanism of action.…”