Nucleic acids as drugs and drug targets: development of oligonucleotide-based drugs and characterization of the mechanism of action of nucleic acid-targeted compounds
The principal lines of research are presented below.
- Thedesign and study of novel drugs selectively targeted at nucleic acids, alone or in complex with specific protein, with potential applications in antitumor, antibacterial or antiviral chemotherapy.
1.1. Design and investigation of novel nucleic acid-selective ligands
Our aim is to design and investigate novel synthetic ligands targeted at specific structural contexts in DNA/RNA chains, in particular those relevant for therapeutic treatment (TAR-RNA of the HIV genome, quadruplex DNA of the human telomeric sequence or of oncogenes). We characterize the physico-chemical parameters of DNA/RNA recognition of established or potential drugs and elucidate the mechanism of action of the new compounds in terms of recognition of specific nucleic acid sequences and interference with the activity of essential helix-tracking enzymes.
1.2. Novel DNA-gyrase and DNA-topoisomerase IV targeted antibacterials
Combinatorial biosynthesis is used for the generation of novel bacterial topoisomerase-inhibiting drugs derived from known and powerful natural inhibitors (especially aminocoumarins, angucyclinones and cyclothialidins) produced by various Streptomyces strains. This approach allows the generation of a variety of novel compounds by the use of recombinant DNA technology. The new derivatives are investigated in view of their use against bacterial strains resistant to existing drugs.
1.3 Novel DNA-topoisomerase I targeted anticancer agents
The design and synthesis of new molecules targeted to the DNA-topoisomerase I complex along with paramagnetic-probe modified derivatives will enlighten the mechanism(s) of the process and allow to plan better anticancer drugs.
- the development of nucleic acids as drugs employing the technique known as SELEX, or Systematic Evolution of Ligands by Exponential enrichment
Selex is an important new methodolof enabling to produce the nucleic acid equivalent of an antibody. Effetive target recongntion may lead to development of novel DNA- and RNA based compounds suitable for both diagnostic and pharmacological applications.
- the molecular mechanism of action of bacterial and human topoisomerases.
Topoisomerases represent a very important family of DNA-processing vital enzymes indispensable for replication and transcription. These proteins require divalent metal ions to perform their catalytic function. We aim at understanding the mechnism(s) of metal ion participation in topoisomerase-mediated processes.