Synthesis of modified PNA probes for sequence-selective G-quadruplex photoalkylation.

01 November 2021 → 31 October 2025
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Bio-organic chemistry
    • Organic chemical synthesis
  • Medical and health sciences
    • Physical pharmacy
Light-triggered furan-based G-quadruplex cross-linking Reaching sequence-selectivity by using peptide nucleic acids (PNAs) Liposomal delivery of PNA constructs
Project description

The inherent propensity of guanine-rich sequences to fold into G-quadruplexes (G4s) is a widely studied phenomenon. These G4s are alternative, secondary nucleic acid structures that have been found in key areas of the genome and transcriptome. Their potential role in the fine regulation of gene expression ultimately indicates their potential as relevant biological targets for drug design. In literature, many small molecules are reported to stabilize, induce and even disrupt the G4-architecture via non-covalent interactions. The OBCR research group recently demonstrated a new alkylation methodology relying on the introduction of a pro-reactive furan moiety in a G4-ligand. Upon red-light irradiation in presence of a co-localized G4-binding photosensitizer, alkylation of the G4 occurred selectively over double-stranded DNA. However, the major issue within this field for the exploitation towards therapeutic applications remains the G4-sequence-specificity. In this PhD proposal, we aim to achieve the sequence-selective cross-linking of one unique G4 in the presence of other G4s by implementing the use of recognition elements in our cross-link methodology, targeting the flanking regions of the G4 structure to bring the ligand in proximity to the desired G4. Our final purpose will be to develop a formulation to deliver our system in a cellular context, using pre-miR-92b as a target to assess our methodology in a biological context.