Award Title: Controlling the protein-protein interactions of telomerase
Funder: The Academy of Medical Sciences

Abstract: This project aims to identify compounds which control the protein-protein interactions (PPIs) in telomerase. This will be achieved by: 1) The preparation of peptides derived from the natural PPI interface and investigation of their telomerase inhibition activity. 2) The synthesis of analogues of these peptides, increasing cell permeability and activity. 3) Implementing peptide directed binding, an efficient method for the generation of small molecule modulators of PPIs. 4) Identifying structural binding modes and design of small molecule leads for preclinical disease models.

Telomeres are repeated sequences of DNA which protect the ends of chromosomes. During DNA replication telomeres are incompletely copied, eventually resulting in senescence. Telomerase is the enzyme responsible for increasing telomeric repeats, maintaining cell proliferation. Telomerase is inactive in normal cells as part of the ageing process, but 90% of cancers exploit this system by activating telomerase, creating an environment for limitless cell division. Inhibiting telomerase has demonstrated good efficacy and selectivity in cancer cells. Targeting telomerase has focussed on nucleic acid-protein interactions generating clinical candidates, but few compounds have fulfilled their promise. Telomerase is made up of several proteins, but disrupting the PPIs remains unexplored.

Recently, the structure of human telomerase was solved, and mutations of diseases which suffer from dysfunctional telomerase were mapped to the structure. Interestingly, the most common mutations mapped to an 11-amino acid α-helix. This infers that modulation of this interface is evolutionarily designed to prevent telomerase activity, and molecules that can control this interaction should selectively target cancer cells.

Lay Abstract: A feature of cancer is an ability to grow continuously and uncontrollably, giving tumours immortality. It does this by overriding our natural ageing process. Our DNA has repeating units on the end that protect our DNA code, like the plastic ends of shoelaces, called telomeres. When cells grow and divide the DNA is incompletely copied, shortening the telomeres. As part of a normal ageing process, when the telomeres are shortened too far the DNA unravels, cells can no longer divide, and die. Cancer uses a complex of proteins called telomerase to add telomeres to the end of DNA, giving tumours immortality.

This project aims to find molecules that control the interactions of the proteins in the telomerase complex. Protein-protein interactions control many diseases, but are challenging for drugs to affect. Proteins are large molecules and drugs are small, like a Chihuahua trying to keep apart sumo-wrestlers. This project will use a new technique, developed by my research group, to make molecules that control the protein-protein interactions of telomerase. First, peptides, small protein-like molecules that look and act like artificial sumo arms, will be made by copying the natural protein structure. Using peptides as scaffolds, and sections can be replaced with drug pieces to make a drug molecule. These new molecules will break apart the telomerase complex, stopping cancer cells from growing uncontrollably and providing a selective treatment for cancers. This new method is cheaper and faster than current techniques to find drugs for protein-protein interactions, meaning treatment reaches more patients.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE