Peptide Nucleic Acids (PNAs) are non-natural DNA mimics, which hybridise with complementary DNA/RNA strands via Watson-Crick base pairing. Due to their neutral peptide backbone, which avoids electrostatic repulsions with negatively charged DNA/RNA strands, PNA-DNA/PNA-RNA duplexes are more stable than the usual DNA-DNA/RNA-RNA duplexes. Another important feature of PNAs is their resistance to attack by proteases and nucleases. Due to these favourable properties, PNAs have been keenly investigated for use in antisense and antigene therapies.
On another research front, bioorganometallics have found, over the last years, application in various areas of medicinal chemistry. One of the most noteworthy of this type of compounds is the ferrocene-chloroquine derivative, Ferroquine, which is currently in phase 2 of clinical trials due to its outstanding antimalarial properties. Not surprisingly, when PNAs were combined with organometallic compounds, the resulting metal-containing PNA bioconjugates obtained were found to have unique chemical/physical properties. These compounds have therefore been explored for various purposes such as biosensing, modulation of PNA-DNA duplex stability, modulation of the cellular uptake of PNAs, DNA-template metal catalysis and designing of radioactive probes.
In this application, the candidate proposes a totally novel approach to specifically and efficiently couple, within a cell, organometallics to PNA oligomers using the cutting-edge "Copper-free" or "Photo" Click Chemistry methodologies. This is unparalleled by any of the current concepts in that the in vitro coupling of any metal complex to any biomolecule has never been explored, to the best of the knowledge of the applicant. The current metal bioconjugation methods available are limited by the toxicity of the catalyst to both bacterial and mammalian cells (e.g. the copper used in the typical Click Chemistry reaction). If successful, the fundamental research described here could have significant implications not only in the bioorganometallic chemistry area but also in vast medicinal and biological areas with tremendous potential applications. For example, it could be envisaged that the specific and time-controlled attachment of an organometallic to a PNA triggers a biological event/process, such as the modification of the secondary structure of a PNA/mRNA duplex leading to a dramatic change in protein expression or modification of the polarity of PNA bioconjugate, inducing a change in its localisation within the cell.