Developing a library of HaloPROTACs targeting the ClpP protease

Nani, Alexandra (2024) Developing a library of HaloPROTACs targeting the ClpP protease. Masters by Research thesis (MSc), Manchester Metropolitan University.

File will be available on: 23 May 2026. Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (3MB)

Abstract

Proteolysis-targeting chimeras (PROTACs) have received recent attention as a new therapeutic agent that have the potential to have a great impact in drug discovery. This project focuses on developing a chemical approach to utilise caseinolytic protease proteolytic (CLpP), a mitochondrial protease, as a potential target for mitochondrial selective PROTACs. The CLp proteases are enzymes that maintain protein homeostasis in both mitochondrial and prokaryotes and have recently been exploited in bacteria for the creation of bacterial specific PROTACs called BacPROTACs. Mitochondria has a similar system to bacteria therefore our aim is to develop PROTACs that bind selectively to to CLpP in mitochondria. In this project we focus our attention on the synthesis of HaloPROTACs, a strategy that can be used as a chemical tool to degrade various targets such as GFP, ERK1, MEK1, CREB1 and c-Jun. We have successfully synthesised 4 HaloPROTACs which consists of a chloroalkane linker and a ClpP binder ligand. Yields ranged between 45% to 55% and the compounds were then purified using column chromatography and the masses were confirmed by LCMS.