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.
My project aims to identify chemically-modified peptides that bind NONO and inhibit telomerase recruitment. In this poster presentation, I will present the successful use of phage display to identify linear peptides that bind NONO with promising in vitro affinities (~1 µM) prior to any optimisation. In addition, I will outline ongoing efforts to develop fragment-bearing peptides that bind NONO, by attaching hits from a fragment-based screening campaign onto phage-displayed peptides using various bioconjugation chemistries.