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.