Structure based peptide design to target the dyskerin dimer protein interaction of telomerase.

A hallmark of cancer is replicative immortality. In 80-90% of cancers this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations alter the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides that inhibit this protein interaction. We developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin demonstrating protein engagement and interaction inhibition. Lead peptides inhibit cell growth in cells that demonstrate higher levels or dyskerin, but do not affect cells with lower levels of dyskerin. These results suggest for the first time inhibition of the protein interactions within the H/ACA RNP offers a new target for broad spectrum cancer treatment.