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Structural NMR investigation of the interaction between metal-based anticancer drugs and RNA

Applicant Donghi Daniela
Number 136726
Funding scheme Ambizione
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.04.2012 - 31.03.2015
Approved amount 407'810.00
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Keywords (5)

RNA; metal-based anticancer drugs; cisplatin; NMR; bioinorganic chemistry

Lay Summary (English)

Lead
Lay summary

Nowadays, many pharmaceuticals contain a metal core, an important class being the metal-based anticancer drugs. Among these, cisplatin is currently a leading agent in clinical use. Besides cisplatin, only two metal-based anticancer drugs are approved for the clinics worldwide, namely carboplatin and oxaliplatin. Despite their effectiveness, these drugs show some drawbacks, like side effects as well as acquired or intrinsic tumor resistance. To face and solve such problems, it is crucial to better understand the mechanisms of action of these drugs.

Cellular DNA is generally recognized as the major biological target for cisplatin and its derivatives. Nevertheless, the interaction with biological targets other than DNA could be responsible for the toxic side effects of the drugs, or could play some still unrevealed role in their anticancer activity. The study of such interaction is essential for the design of more effective drugs.

The involvement of RNA in many biological processes makes this nucleic acid an attractive target for pharmacological intervention. Nonetheless, studies aimed at designing of RNA-targeting drugs have started only recently, as a consequence of the relatively recent discovery of the variety of RNA, its abundance, and its manifold role in cell biology. Cisplatin has been shown to interact with various RNAs, but the available reports are based on biochemical studies only, and no structural investigation in solution has been performed so far.

Structural studies of such interactions are crucial to design new drugs able to selectively target specific structural motifs, and to overcome the actual limitations of the drugs in clinical use.

This project focuses on the structural characterization of the interaction between metal-based anticancer drugs and isolated functionally-relevant domains of a group II intron ribozyme as model RNA, using nuclear magnetic resonance (NMR) spectroscopy. Group II introns contain structural features common to many RNAs, and allow for a direct structure-function relationship based on their catalytic activity. Thus they are ideal systems to investigate RNA-metal complexes interaction.

This study is expected to reveal sequence and structure preferences of the drugs, as well as specificity in the mode of actions, thus opening up new perspectives in the design of RNA-targeting metal-based drugs.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Application of Heteronuclear NMR Spectroscopy to Bioinorganic and Medicinal Chemistry
Donghi Daniela, Ronconi Luca (2014), Application of Heteronuclear NMR Spectroscopy to Bioinorganic and Medicinal Chemistry, in Jan Reedijk (ed.), Elsevier, Waltham, MA, n.a..
NMR Spectroscopy in Bioinorganic Chemistry
Donghi Daniela, Johannsen Silke, Sigel Roland K. O., Freisinger Eva (2012), NMR Spectroscopy in Bioinorganic Chemistry, in CHIMIA, 66(10), 791-797.

Collaboration

Group / person Country
Types of collaboration
Prof. Sofi K.C. Elmroth, Biochemistry and Structural Biology, KILU, Lund University Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
7th Asian Biological Inorganic Chemistry Conference (AsBIC7) Talk given at a conference Investigation of metal complex binding to RNA 30.11.2014 Gold Coast, Australia Donghi Daniela;
12th European Biological Inorganic Chemistry Conference (EuroBIC12) Talk given at a conference Investigation of metal complexes-RNA interaction 24.08.2014 Zurich, Switzerland Donghi Daniela;
EUROMAR 2014 Poster Interaction between RNA and metal complexes studied by NMR 29.06.2014 Zurich, Switzerland Donghi Daniela;
Young Faculty Meeting 2014 of the Swiss Academy of Sciences (SCNAT) "Platform Chemistry" Talk given at a conference Targeting RNA with metal complexes 05.06.2014 Bern, Switzerland Donghi Daniela;
Magnetic Resonance for Cellular Structural Biology, EMBO Workshop Poster Metal complexes as potential RNA targeting agents 01.06.2014 Principina Terra, Grosseto, Italy Donghi Daniela;
1st International Symposium on Functional Metal Complexes that Bind to Biomolecules (2nd WHAM of the COST Action CM1105) Talk given at a conference Platinated RNA duplexes: preparation and NMR studies 09.09.2013 Barcelona, Spain Donghi Daniela;
XII International Symposium on Inorganic Biochemistry Poster Influence of platinum drugs on RNA structure 28.08.2013 Wroclaw, Poland Donghi Daniela;
RNA 2013, the 18th Annual Meeting of the RNA Society Poster How do platinum drugs interact with RNA? 11.06.2013 Davos, Switzerland Donghi Daniela;
COST Action CM1105 - Working Group 2 Meeting Talk given at a conference RNA and platinum drugs 05.03.2013 Birmingham , Great Britain and Northern Ireland Donghi Daniela;
First Whole Action Meeting COST Action CM1105 Poster Investigation of the interaction between metal-based anticancer drugs and RNA 17.09.2012 Granada, Spain Donghi Daniela;
11th European Biological Inorganic Chemistry Conference (EUROBIC11). Poster Interactions between platinum drugs and RNA 12.09.2012 Granada , Spain Donghi Daniela;


Self-organised

Title Date Place
2nd International Symposium on Functional Metal Complexes that Bind to Biomolecules (3rd WHAM of the COST Action CM1105) 22.08.2014 Zurich, Switzerland

Awards

Title Year
Best Poster Award- 11th EUROBIC (Granada, Spain, 12-16 September 2012) 2012

Abstract

The serendipitous discovery of the antitumor activity of cisplatin (cis-diamminedichloroplatinum(II)) in the late sixties stimulated the use of coordination chemistry to design new metal-based anticancer drugs.Nevertheless, cisplatin has remained one of the leading metal-based anticancer agents to date.Although the interaction between platinum drugs and DNA is often accounted for their anticancer activity, only small amounts of the drug seem to enter the nucleus, and the rest is likely to interact with other species, like cell membrane ligands, peptides, proteins and RNA. Even if for long time neglected, the study of the interaction of cisplatin and related drugs with biologically relevant molecules other than DNA is crucial to understand the bio-distribution and pharmacokinetics of the drugs, as well as their toxicity. In this regard, in the last few years several studies on the interaction between platinum drugs and proteins have been published.Only recently RNA has been proposed as drug target, after the relatively recent discovery of its variety and abundance, as well as of its multiple roles in crucial biological processes. It has been already reported that some RNA-dependent activities, such as translation and splicing, are inhibited upon administration of platinum drugs, but little is known on the effects of platination on RNA biology to date. However, in the last few years, the interaction of cisplatin with RNA has rapidly gained a high interest within the scientific community. The first goal of this project is to study the influence of platinum anticancer drugs on the local structure of RNA by NMR spectroscopy. Different biologically relevant regions of the yeast mitochondrial group IIB intron ribozyme Sc.ai5gamma will be used as target RNAs. Group II introns are large catalytic RNAs, considered ancestors of the eukaryotic spliceosome. The most prominent reaction catalyzed by these ribozymes is their own splicing, followed by ligation of the exonic parts, performed in a manner that resembles the spliceosome. Their structure is formed by six domains that must adopt a specific 3D architecture to carry out their function. The solution structure of the functionally relevant domains 5 and 6 has been published in the last few years. These two RNA fragments contain structural motifs common to other RNAs, and are ideal systems to investigate RNA-metal complexes relationship. The modification of their structure upon platinum binding will be investigated in details by NMR spectroscopy. This is to the best of our knowledge the first time that such structural studies are planned. Our anticipated results will represent a necessary and essential starting point for future research, aimed at studying the interaction between RNA and different anticancer metal-based drugs.The second part of the project deals with the influence of cisplatin on the biological functions of the group IIB intron ribozyme Sc.ai5gamma. NMR and biochemical studies are planned to evaluate the effect of platination at specific sites on the formation of the catalytic core and on the splicing of this ribozyme.In general, the proposed research, besides giving further insights into the intricate world of anticancer metal-based drugs and nucleic acids interaction, might provide crucial information for the design of new RNA-targeting drugs.
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