Telomeres are repetitive nucleoprotein structures that cap the ends of chromosomes and limit cell division. Each round of division shortens telomeres until a critical length is reached, triggering the DNA damage response and leading to cellular senescence or apoptosis1. Approximately 85-95% of cancers maintain telomere length and acquire immortality by reactivating and recruiting telomerase to synthesise more telomeric repeats1. Telomerase recruitment is regulated by the Drosophila behaviour/human splicing (DBHS) family of proteins – NONO, SFPQ, and PSPC1. A recent study showed that long-term NONO depletion results in progressive telomere shortening in cancer cells, providing a novel therapeutic pathway to target telomerase-positive cancers2.
In this presentation, I will describe the identification of the first reported peptide ligands of NONO using phage display, with a lead peptide exhibiting promising in vitro binding affinities (~1 µM) prior to optimisation. I will present experimental data probing the interaction of the lead peptide, with results consistent with a disulfide-dependent binding mode. Alanine scanning and cysteine mutagenesis were performed to identify key residues contributing to binding and to assess the potential for future modification. In parallel, truncation studies were conducted to define a minimal peptide sequence that retains binding affinity. Finally, I will present data from fragment-based phage screens, in which fragment hits were appended to phage-displayed peptides, providing insights into NONO-binding chemical space.