Elucidating the role of a novel oxygen sensing pathway in health and disease

Molecular oxygen is a vital biological resource, delivery of which is impaired in many diseases due to inadequate blood perfusion. As a result, oxygen depravation (hypoxia) contributes to some of the leading causes of death and disability in developed countries, including ischemic heart disease and cancer. To help address these therapeutic challenges, the molecular mechanisms underpinning oxygen homeostasis and hypoxic adaptation have been targeted to beneficially alter low oxygen stress response.

This project uses biochemistry, structural biology, proteomics, cell biology, and drug discovery to investigate the properties, function, and pathology of 2-aminoethanethiol dioxygenase (ADO), a novel enzymatic oxygen-sensor, which controls the oxygen-dependent stability of proteins bearing an N-terminal cysteine through the N-degron pathway of proteasomal degradation.

Collaborators include Dr Kristina Cook and Professor Richard Payne

Developing an enzymatic toolkit for the late-stage functionalisation of bioactive peptides

Cyclic peptides are fundamental bioactive natural products, which play essential roles in medicine and agriculture as antibiotics and biopesticides. However, target resistance and experimental stagnation has limited the number of viable molecules available, threatening our ability to treat infections and produce food. While the identification of novel candidates with unique mechanisms of action is critical for long-term resolution, translation of this research is often protracted and underfunded, creating a need to revitalise current approaches and agents.

This project will produce a series of flavin- and non-heme iron-dependent halogenases, which can catalyse the late-stage functionalisation of culturally and commercially important cyclic peptides through semi-rational protein engineering so that their chemical properties and bioactivities can be enhanced through chemoenzymatic modification. Tryptophan, tyrosine and threonine halogenases will be explored to increase utility, with the halogen group acting as both a standalone alteration and a handle for additional synthetic modification (e.g. through Suzuki coupling).

Prospective candidates and important substrate binding features have been identified through bioinformatics and structural analysis, with a directed evolution campaign against initial scaffolds planned.

Collaborators include Dr Constance Bailey

Developing novel proteolysis-targeting chimeras (PROTACs) for conditional target degradation

Targeted protein degradation is an exciting therapeutic strategy in which pathological cellular targets are removed using heterobifunctional molecules called proteolysis-targeting chimeras (PROTACs), which recruit an E3 ligase and promote ubiquitin-mediated proteosomal degradation. This allows traditionally undruggable disease targets, which don't contain a functionally defined binding or active site, to be eliminated.

This project uses medicinal chemistry, biophysics, structural biology, and cell biology to develop novel PROTACs, which degrade targets under specific biological conditions to increase therapeutic control.

Collaborators include Dr Jonathan Danon

Developing chemical tools to treat hypoxic disease and enhance crop food tolerance

Molecular oxygen is a vital biological resource, delivery of which is impaired in many human diseases due to inadequate blood perfusion. This creates or exacerbates pathological conditions by detrimentally altering the biochemistry and behaviour of affected cells. Accordingly, oxygen deprivation (hypoxia) contributes to some of the leading causes of death in developed countries, including stroke, ischemic heart disorders, and cancer. Hypoxia also impacts plant growth and survival during flooding, as water limits oxygen diffusion from the atmosphere. This significantly reduces crop yield, threatening food security, particularly in the context of climate change, which is increasing the frequency and magnitude of extreme weather events. Accordingly, the molecular mechanisms underpinning oxygen homeostasis and hypoxic adaptation have emerged as viable intervention points to combat therapeutic and agrichemical challenges associated with low oxygen stress.

This project will help develop chemical modulators of a novel enzymatic oxygen sensing system found in both animals and plants to help treat hypoxic disease and generate flood tolerant crops.

This project uses in silico screening, fragment-based drug discovery, mRNA display, cyclic peptide inhibitor optimisation, and rational design using structural information.