Ph. D. Project
Title:
Modeling and study of the genomic selectivity of next-generation G-quadruplex(G4) ligands in cancer models
Dates:
2026/01/07 - 2029/01/06
Supervisor(s):
Other supervisor(s):
MONARI Antonio (antonio.monari@u-paris.fr)
Description:
G-quadruplexes (known as G4s) form from guanine-rich sequences of DNA or RNA, folded into four-stranded secondary structures. G4s consist of four guanines in planar Hoogsteen pairing, generating G4 tetrads, stacked on top of each other and stabilized by the presence of a monovalent cation (usually K+ or Na+). These DNA G4 structures can adopt a variety of topologies (parallel, antiparallel, or hybrid) according to the strand direction and the mode of intramolecular or intermolecular interactions of the DNA and/or RNA. G4s are tertiary, dynamic, and transient structures of nucleic acid strands. The existence of G4s, their locations in functional genomic regions and in the 5'-untranslated regions of RNAs, demonstrate their importance in the regulation of major cellular and molecular processes such as transcription, translation, replication, epigenetic and telomeric regulation. The role of G4s has also been demonstrated in the development of various human diseases, from neurodegenerative disorders to cancers. In the latter, G4s have been mapped on various oncogene promoters and are found enriched in tumors.
In this biomedical context, numerous natural or synthetic G4 ligands has been identified so far, some of which shown cytotoxic effects with a promising therapeutic potential. However, their selectivity, regarding to the topology of G4 structures, remains poorly characterized. Our current work has identified new Schiff base-based G4 ligands (synthesized by G. Barone's team (Bioinorganic Team, University of Palermo)), demonstrating differences of in-vitro G4 stabilization potentially linked to G4 topology.
To optimize the stabilization and action of these new G4 ligands at the cellular level, our CANDI4G4 project proposes to first model the interactions of these ligands with G4 structures of different topologies and genomic origins. This initial modeling step will help us to characterize this topological selectivity and also propose modified ligand models to increase their topological selectivity. Finally, in a second stage, these selected G4 ligands will be characterized and validated by high-throughput genomic mapping in cellular cancer models. The multidisciplinary CANDI4G4 project, at the interface of inorganic chemistry and biology, aims to investigate the stabilization selectivity of these new G4 ligands at the genome-wide level. It will also provide a better understanding of the stabilization capacity of these next-generation G4 ligands according to G4 topology.
In this biomedical context, numerous natural or synthetic G4 ligands has been identified so far, some of which shown cytotoxic effects with a promising therapeutic potential. However, their selectivity, regarding to the topology of G4 structures, remains poorly characterized. Our current work has identified new Schiff base-based G4 ligands (synthesized by G. Barone's team (Bioinorganic Team, University of Palermo)), demonstrating differences of in-vitro G4 stabilization potentially linked to G4 topology.
To optimize the stabilization and action of these new G4 ligands at the cellular level, our CANDI4G4 project proposes to first model the interactions of these ligands with G4 structures of different topologies and genomic origins. This initial modeling step will help us to characterize this topological selectivity and also propose modified ligand models to increase their topological selectivity. Finally, in a second stage, these selected G4 ligands will be characterized and validated by high-throughput genomic mapping in cellular cancer models. The multidisciplinary CANDI4G4 project, at the interface of inorganic chemistry and biology, aims to investigate the stabilization selectivity of these new G4 ligands at the genome-wide level. It will also provide a better understanding of the stabilization capacity of these next-generation G4 ligands according to G4 topology.
Keywords:
molecular dynamics, G-quadruplex, cancer, genome-wide, DNA, RNA, ligands, therapy
Department(s):
| Biology, Signals and Systems in Cancer and Neuroscience |