Our research is focussed on using synthetic chemistry to provide new tools and strategies to understand and manipulate biological systems. A long standing collaboration with Prof Alison Baker uses these tools to understand and manipulate peroxisomes – key eukaryotic organelles with a dedicated protein trafficking pathway. Synthesising probes and characterising the biophysics of their interactions with key components of the trafficking machinery has led to new insights into the trafficking process and enabled us to manipulate the pathway. In collaboration with Prof Adam Nelson we have also developed Activity Directed Synthesis as a novel platform for the efficient discovery of bioactive scaffolds – exploiting parallel synthesis and promiscuous chemistry to discover new modulators of a number of important biological processes. All of our projects employ our expertise in synthesis and analytical chemistry, particularly around mass spectrometric analysis.
Current major projects
- Understanding and manipulating peroxisomal protein Import
- Subverting the peroxisome for synthetic biology
- Developing efficient methods for bioactive molecule discovery
Detailed research programme
Understanding Peroxisomal Protein Import
Peroxisomes are remarkable organelles that import their protein complement from the cytosol using a dedicated protein import pathway. Our studies are particularly focussed on the PTS1 import pathway characterising the thermodynamics of the import process as well as developing probes that can interrogate the individual steps within the pathway to provide more detail on how the import process functions.
Subverting the Peroxisome for Synthetic Biology
Using our knowledge of the peroxisomal import process we have developed methods to engineer the import process, developing orthogonal import signals and receptors allowing us to hijack the peroxisomal import process in moss cells. This enables us to change the components of the peroxisome away from those found naturally and to exploit the peroxisome as a bespoke compartment within the cell. We are developing these tools in other organisms for application in synthetic biology.
Activity Directed Synthesis
The traditional methods for the discovery of bioactive molecules where compounds are synthesised, purified and screen impose hidden constraints on the chemistry that is used to make the molecules. Productivity drivers steer chemists towards high yielding predictable reactions which in turn impacts on the structural diversity of the resulting compounds. In Activity Directed Synthesis we use reactions with inherently unpredictable outcomes to generate libraries of compounds which can be rapidly screened for activity. Active mixtures then inspire the development of compounds in subsequent rounds of development.