Oxaliplatin vs. cisplatin: competition experiments on their binding to lysozyme

Marasco, Daniela; Messori, Luigi; Marzo, Tiziano; Merlino, Antonello

doi:10.1039/c5dt01279a

Cited by 48 publications

(35 citation statements)

References 43 publications

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“…Furthermore, oxaliplatin can also bind, with low occupancy, the NE2 atom of His105. These results are interesting since it has been previously shown, by studying its interaction with HEWL, that oxaliplatin preferentially binds Asp side chains [24], while both carboplatin and cisplatin show a preference for His side chains [12,46]. This is even more surprising if one takes into account that the oxaliplatin fragment bound to RNase A is larger than those of carboplatin and cisplatin.…”

Section: Discussionmentioning

confidence: 53%

Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts

Messori

Marzo

Merlino

2015

Journal of Inorganic Biochemistry

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Oxaliplatin and carboplatin are two platinum(II) drugs in widespread clinical use for the treatment of various types of cancers; yet, structural information on their interactions with proteins is scarce. Here, the X-ray structures of the adducts formed upon reaction of carboplatin and oxaliplatin with bovine pancreatic ribonuclease (RNase A) are reported and compared with results obtained for the structure of the RNase A-cisplatin adduct derived from isomorphous crystals, under the same experimental conditions. Additional details on the binding mode of these metallodrugs toward RNase A are provided by electrospray ionization mass spectrometry (ESI MS) measurements, thus offering insight on the occurring metal-protein interactions. Notably, while carboplatin and cisplatin mainly bind the side chain of Met29, oxaliplatin also binds the side chains of Asp14, of catalytically important His119 and, to a lesser extent, of His105. On the basis of the available data, a likely mechanism for oxaliplatin hydrolysis and binding to the protein is proposed. These results are potentially useful for a better understanding of the biological chemistry, toxicity and side effects of this important class of antitumor agents.

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Section: Discussionmentioning

confidence: 53%

Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts

Messori

Marzo

Merlino

2015

Journal of Inorganic Biochemistry

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“…S4A). Crystal structures lacking expected ligands are not unprecedented (21,22). Furthermore, a Zeise's salt co-crystal with similar coordination geometry shows two aqua ligands in the trans positions (supplemental Fig.…”

Section: Binding Of Platinum Compounds To Reca Intein Depends On the mentioning

confidence: 99%

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

Chan

Pearson

Green

et al. 2016

Journal of Biological Chemistry

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Inteins, self-splicing protein elements, interrupt genes and proteins in many microbes, including the human pathogen Mycobacterium tuberculosis. Using conserved catalytic nucleophiles at their N-and C-terminal splice junctions, inteins are able to excise out of precursor polypeptides. The splicing of the intein in the mycobacterial recombinase RecA is specifically inhibited by the widely used cancer therapeutic cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ], and this compound inhibits mycobacterial growth. Mass spectrometric and crystallographic studies of Pt(II) binding to the RecA intein revealed a complex in which two platinum atoms bind at N-and C-terminal catalytic cysteine residues. Kinetic analyses of NMR spectroscopic data support a two-step binding mechanism in which a Pt(II) first rapidly interacts reversibly at the N terminus followed by a slower, first order irreversible binding event involving both the N and C termini. Notably, the ligands of Pt(II) compounds that are required for chemotherapeutic efficacy and toxicity are no longer bound to the metal atom in the intein adduct. The lack of ammine ligands and need for phosphine represent a springboard for future design of platinum-based compounds targeting inteins. Because the intein splicing mechanism is conserved across a range of pathogenic microbes, developing these drugs could lead to novel, broad range antimicrobial agents.Inteins, self-splicing protein elements that invade a host gene, have been of great interest to the field of biotechnology. The unique ability of an intein to break and form peptide linkages has led to their use in applications (1, 2) ranging from sensors of small molecules (3, 4) and environmental conditions (5) to single step protein purification platforms (6, 7). However, there are still underexplored reactions involving native inteins, notably their susceptibility as targets for antimicrobial drugs (8). In nature, inteins reside in key host proteins across several bacterial and fungal pathogens, including Mycobacterium tuberculosis, Mycobacterium leprae, and Cryptococcus neoformans (9).These splicing elements divide the host protein into two parts, termed N-and C-exteins on the corresponding ends of the intein. In the precursor form, the host protein is usually non-functional because of the tendency of an intein to insert into highly conserved functional regions of the protein. In M. tuberculosis, inteins occur in three genes, recA, sufB, and dnaB (9). The functionality of these proteins is key to the survival of the bacterium and relies upon the splicing of the intein from the respective host proteins. Because inteins do not occur in multicellular organisms, prevention of protein splicing provides a promising strategy for the development of novel antimicrobial therapeutics.Canonical intein splicing occurs by a multistep process (10). First, a nucleophilic attack is initiated by the N-terminal cysteine residue (C1) of the intein on the preceding peptide bond, resulting in thioester formation (Fig. 1A, step 1). A second nucleophilic a...

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“…46,47 These results also indicate that it is in principle possible to obtain a mixed Pt-based drug encapsulated AFt, i.e., a protein cage with both CDDP and CBDCA bound in the core of the protein, as done for the bis-adduct formed in the competitive reaction between cisplatin and oxaliplatin with hen egg white lysozyme, where the two Pt-based drugs are concomitantly bound to the protein. 48 ■ ASSOCIATED CONTENT…”

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confidence: 99%

X-ray Structure of the Carboplatin-Loaded Apo-Ferritin Nanocage

Pontillo

Ferraro

Helliwell

et al. 2017

ACS Med. Chem. Lett.

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The second-generation Pt anticancer agent carboplatin (CBDCA) was encapsulated within the apo horse spleen ferritin (AFt) nanocage, and the X-ray structure of the drug-loaded protein was refined at 1.49 Å resolution. Two Pt binding sites, different from the one observed in the cisplatin-encapsulated AFt, were identified in Ft subunits by inspection of anomalous electron density maps at two wavelengths and difference Fourier electron density maps, which provide the necessary sensitivity to discriminate between Pt from CBDCA and Cd ions that are present in the crystallization conditions. Pt centers coordinate to the NE2 atom of His49 and to the NE2 atom of His132, both on the inner surface of the Ft nanocage.

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Oxaliplatin vs. cisplatin: competition experiments on their binding to lysozyme

Cited by 48 publications

References 43 publications

Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts

Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

X-ray Structure of the Carboplatin-Loaded Apo-Ferritin Nanocage

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