Final Report Summary - NOSETI2 (Novel Oligonucleotide-based Strategies for Efficient Telomerase Inhibition)
Executive Summary:
The Project NOSETI2 has been aimed at the synthesis of small-molecule conjugates as chemical tools to study human telomerase inhibition, with potential applications in the treatment of cancer and age-related diseases. In particular, the project has addressed the chemical synthesis of different metal complexes bound to DNA recognizing motifs (such as oligonucleotides, saccharide, polyamines, and heterocyclic compounds) able to bind to the telomere G-quadruplex DNA sequence. It also included the characterization, by biochemical and spectroscopic methods, of the interaction between the novel synthesized molecules and a model system based on oligonucleotides mimicking the DNA sequence of the telomere, under physiological conditions. A final goal of the project has been the preliminary in vitro evaluation of the biological activity of these novel molecules to establish their potential as cancer therapeutics. Research in this field is crucial, especially within the context of the EU work programs, taking into account the world-wide prevalence of cancer as a deadly disease.
During the execution period of this project, the chemical synthesis of several selective G-quadruplex DNA ligands capable of recognizing the telomeric DNA sequence has been accomplished. These ligands were based on heterocyclic systems that can be complexed to metals. As heterocyclic systems, 1,10-phenanthroline and 2,2’-bipyridine have been employed. As metal ions, we have mainly concentrated on copper complexes, although some other complexes, involving divalent platinum, palladium and nickel atoms have also been synthesized. Different attempts have been made to conjugate the metal complex core to molecules of biological relevance, such as oligonucleotides, monosaccharides, aminoacids, nitrogen-rich alkyl chains containing terminal guanidinium groups, or heterocycles. Interaction studies with synthetic oligonucleotides containing the human telomere sequence mimicking physiological conditions have revealed optimal properties, in terms of affinity and selectivity, which is suggestive of their potential future use as telomerase inhibitors. In the long term, several applications in cancer chemotherapy could be derived from complete biochemical characterization and biological activity determination.
Moreover, the NOSETI2 project has notably contributed to the career development of the IRG Marie Curie fellow by providing a funded scheme that has allowed the fellow to explore her research interests and to gain a good degree of scientific independence. Some of the consequences of the implementation of this action have been the setup of a new line of investigation within the research group at the host institution, as well as the training of several young researchers, the mobility of the researchers within the European Union and the establishment of scientific collaborations within the context of this project. Finally, the action has resulted in a successful reintegration of the fellow, who has been kept employed as a faculty member by the host institution beyond the end date of the project.