CORDIS - EU research results
CORDIS

In vitro and In-cell characterization of Quadruplex-duplex hybrids: conformation, folding, and recognition by drug-like ligand molecule

Project description

Characterisation of nucleic acid quadruplex−duplex hybrids and their targeting by drug-like ligands

Nucleic acids are polymorphic, and guanine-rich nucleic acid sequences can form G-quadruplex (G4) structures in addition to classic duplexes. The formation of G4 structures was shown in vitro in solutions and cells, where they presented attractive targets for small molecules. Recent studies suggest that G4 folding may differ in the cellular environment due to the limitation of the components. Funded by the Marie Skłodowska-Curie Actions programme, the QDHassay project aims to develop specific G4 drugs targeting G4 quadruplex−duplex hybrids (QDH). The project will use low- and high-resolution spectroscopy as well as ligand screening based on mass spectrometry to characterise ligand−QDH interaction. The final goal is to develop an in-cell nucleic acid folding spectroscopy analysis method and a ligand screening assay inside the cellular system.

Objective

"Nucleic acids are intrinsically polymorphic. Apart from the Watson-crick duplex, guanine-rich sequences can form G-quadruplex (G4) structures, which have become attractive targets for small molecule ligands. It is now proven that G-quadruplexes can form in cells. Today most biophysical and structural/ligand binding studies are carried out in dilute aqueous solutions and the presence of artificial crowding agents/cosolvents. Still, recent works suggest that the folding of G4s may differ in the cellular milieu context due to the agents' limitations. Thus there is an immense need for in-cell-based structural biology approaches. In the proposal, I aim to address critical milestones leading to the bioactive conformation inside the cell and the development of effective/specific G4 targeting drugs using an essential sub-class of G4 structures as a paradigm, namely quadruplex−duplex hybrids (QDH-hereafter). We will focus on low- and high-resolution spectroscopic approaches and mass spectrometry-based ligand screening assays characterizing ligand-QDH interaction. On the methodological part, we will develop in-cell NMR in ""native"" conditions (starting from unfolded conformation: denovo folding) and propose a ligand screening assay inside the cellular system. Our project will contribute to unveil fundamental principles of nucleic acid folding. It will also foster collaboration between two European institutes specialized in complementary biophysical and structural approaches to study biomolecular folding. In a nutshell, the Maria Skłodowska Curie fellowship will flourish my scientific excellence and the resilience needed for my original ideas to become a reality and communication and public engagement skills across cultures and disciplines."

Funding Scheme

MSCA-PF - MSCA-PF

Coordinator

Masarykova univerzita
Net EU contribution
€ 166 278,72
Address
Zerotinovo namesti 9
601 77 Brno
Czechia

See on map

Region
Česko Jihovýchod Jihomoravský kraj
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data

Partners (1)