Conformationally locked G4-decoy oligonucleotides for selective telomerase inhibition and development of a nucleic acid-based anti-telomerase PROTAC strategy

01 October 2022 → 30 September 2025
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Macromolecular and materials chemistry not elsewhere classified
    • Medicinal and biomolecular chemistry not elsewhere classified
    • Bio-organic chemistry
    • Organic chemical synthesis
    • Nucleic acids
Decoy strategy Telomerase G-Quadruplex PROTAC
Project description

G-Quadruplex (G4) nucleic acids have received increasing attention not only as targets for small molecule or oligonucleotide-based therapeutic strategies but also due their use as therapeutic aptamers (e.g. AS1411, in clinical trials as anti-nucleolin aptamer), given their known binding to transcription factors and other DNA-binding proteins. An exceptionally relevant target in this field is telomerase, an enzyme that is overexpressed in cancer cells. Many small-molecule G4-binding ligands for telomerase inhibition have been synthesized, but none of them succeeded clinical trials, mainly due to selectivity issues. Here, we aim at developing an entirely new approach for human telomerase inhibition. By introducing modifications to covalently “staple" a human-telomeric structure-switching G4-DNA, we will strive at selective stabilization of the parallel G4 conformation in order to maximize its interaction with the enzyme. Different chemistries for intrastrand covalent bond formation will be considered, as well as additional structural variations (use of synthetic nucleosides, such as LNAs), to ensure stable binding of our decoy G4 to the target enzyme, ultimately resulting in inhibition of telomerase activity. In the last and most challenging part of the project, we aim at delivering the first example of a G4-based PROTAC approach by linking the best-performing stabilized G4 analogue to an E3-ligase ligand, for further ubiquitination and proteasome degradation of telomerase.