Selective inhibitors of E3 ubiquitin ligases to treat neurodegenerative diseases

The ubiquitin system is a biological regulatory mechanism found within all cells. It involves the transfer of the small protein ubiquitin, a process known as ubiquitylation, to other substrate proteins which in turn regulates their stability, activity or localization. The ubiquitin system regulates almost all aspects of biology and is implicated with diseases ranging from cancer, autoimmune disorders, and neurodegeneration. Pivotal enzymatic regulators of the ubiquitin system are ubiquitin E3 ligases (E3s) which determine which proteins will be ubiquitinated. There are >600 E3s present in humans and selectively modulating their activity has enormous potential for meeting a number of unmet clinical needs.
Therapeutic strategies for modulating E3s are in their infancy and novel innovative approaches are needed that are likely to be quite distinct from those currently adopted for well-established enzyme targets. This PhD project will explore a number strategies for selectively modulating the activity of key members of the E3 ligase family that are involved in neurodegeneration. This will be leveraged with E3 activity profiling technology the lab has recently developed that will enable facile characterisation of inhibitor potency and selectivity. The project will suit a candidate who has recently carried out undergraduate training in chemistry or a related subject. The nature of the research will be multidisciplinary combining elements of synthetic chemistry, cell biology and structural biology.

Project provides training in Interdisciplinary Skills.