- Professor of Organic Chemistry
- Areas of expertise
- Protein-Protein Interactions; Chemical Biology; Aggregation Mechanisms; Chemical Protein Labelling; Enabling Drug Discovery Methods
- +44(0)113 343 1409
- G.15 Chemistry
- Engineering and Physical Sciences
Protein-protein interactions (PPIs) mediate all cellular processes, play a central role in disease and represent the majority of interactions in the human interactome. Thus, a major problem in life-sciences research is to understand and manipulate PPIs with molecular and temporal resolution – this would allow the identification of the transient intermediates that play key roles in the function of biomacromolecular machines, signalling, translocation and folding. In turn this understanding will illuminate our understanding of disease development e.g. cell signalling in cancer and aggregation in amyloid disease and provide starting points for drug-discovery. Developing capability to understand and control PPIs is thus a significant challenge of immense therapeutic importance. However, methods to interrogate and manipulate PPIs are not well established. Moreover, intrinsically disordered regions – segments of protein with no fixed structure – that undergo disorder-to-order transitions upon formation of the PPI, compound this challenge. The Wilson group uses chemical biology approaches to study and manipulate PPIs, focusing on enabling methods for drug-discovery, protein labelling, assembly mechanisms and structural molecular biology. Current targets include: p53/hDM2, BH3/BCl-2 family, HIF-1α/p300, interactions of Aurora kinase, and interactions of 14-3-3 proteins, (all oncology), GKAP/SHANK-PDZ (synaptic function), SIMS/SUMO (SUMOylation is a regulatory post-translational modification), β2M and Aβ1-40/42 aberrant aggregation.
Current major projects
- Enabling computational and synthetic methods to understand and modulate protein-protein interactions for drug discovery
- Chemical Protein Labelling methods for Structural Proteomics and Dynamic Interactome Analysis
- Understanding amyloid assembly mechanism using chemical biology approaches.
Detailed research programme
Enabling computational and synthetic methods to understand and modulate protein-protein interactions for drug discovery
Developing chemical probes to interrogate cell-signalling pathways represents a significant challenge of immense biochemical and medical importance. However, methods to competitively inhibit PPIs using small molecules are not well established, given that they must cover 800-1100Å2 of a protein surface and complement the discontinuous projection of hydrophobic and charged domains over a flat or moderately convex surface. We are interested in developing integrated approaches to the discovery of effective, low molecular weight PPI inhibitors that use in silico design, synthesis and biophysical evaluation as its pillars. We develop novel constrained peptide, peptidomimetic, fragment and small-molecule mimics of protein secondary and tertiary structure guided by experimentally validated hot-residue prediction and other state of the art computational methods.
Chemical Protein Labelling methods for Structural Proteomics and Dynamic Interactome Analysis
Understanding the mechanistic role of proteins and their macromolecular complexes in signalling pathways requires the capability to study their structural interactome and localisation with temporal resolution. Our group are developing synthetic protein labelling chemistry that can provide solutions for these problems, including methods that allow (i) a label to be transferred from one protein, peptide or small-molecule ligand to its protein partners or (ii) the use of a photocatalytic ligand to induce selective and proximity dependent labelling of a protein target with a third labelling reagent. Ongoing development of these methods and application to cellular systems could support understanding of target biology earlier in drug discovery programs to reduce attrition in the more costly stages of clinical testing.
Understanding Amyloid Assembly Mechanism using Chemical biology approaches
Molecular mechanisms of peptide and protein assembly reactions are not well understood. Ongoing studies in our group are focussed on developing integrated chemical biology methods that comprise a suite of biochemical and computational tools together with state-of the art mass-spectrometry to study amyloid assembly. At the core of this approach is the cross-linking of diazirines which upon excitation generate highly reactive carbenes to encode non-covalent structure in cross-linked peptides. These approaches have recently been harnessed to provide, for the first time, an analysis of the structural mechanism of surface-catalyzed secondary nucleation in amyloid assembly. Ongoing research is also focussed on developing chemical probes that can be used to understand amyloid assembly reactions and providing starting points for therapeutics development.