Developing Therapies for Prion Diseases
Prion diseases are transmissible neurodegenerative diseases. They are always fatal, and currently there exists no effective therapy in combating these diseases. As they can cross the species barrier as seen with bovine spongiform encephalopathy – mad cow disease – developing therapies for prion diseases will have both medicinal and veterinary impact. The infectious prion protein (PrPSc) uses the native protein (PrPC) as a template to spread the disease. Removal of this template by targeted degradation of PrPC should halt the disease in its tracks, avoiding the toxic formation of plaques and amyloids found in the CNS.
The specific method used to target and degrade PrPC in this project is through PROTAC technology – PROteolysis TArgeting Chimera. A PROTAC consists of two moieties bound by a molecular linker; one moiety binds to the protein of interest, PrPC, and the other binds to an E3 ubiquitin ligase. This effectively enables the hijacking of the ubiquitin-proteasome system, tagging PrPC with ubiquitin and signalling for its degradation via the proteasome. The objective of my work is to synthesise a series of PROTACs to test both in vitro and in cells.
Computational studies have been completed to design a family of PROTAC ligands that will bind to PrPC. These have now been successfully synthesised and are now undergoing biophysical and cellular evaluation to determine their potential.