Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.

Abstract

A hallmark of cancer is the ability to replicate limitlessly making them immortal. In 80-90% of cancer cells 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 are transcribed to 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, and developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin. Lead peptides were able to bind to dyskerin, prevent the dyskerin/dyskerin interactions. They inhibit cell growth in MCF-7 cells that demonstrate above average dyskerin expression but were unable to affect A549 cells with below average dyskerin expression. Results suggest inhibition of the protein interactions within the H/ACA RNP offer a new target for broad spectrum cancer treatment.