The Wilson group is interested in the application of synthetic molecules to problems in Chemical Biology and Nanotechnology.
Specific problems include:
- Development of small molecules that bind to protein surfaces and inhibit protein-protein interactions such as the p53-HDM2 interaction – an important cancer target
- Development of molecular probes that can be used to unravel mechanistic details of biological self-assembly processes e.g. amyloid formation
- Development of small molecules with well-defined self-assembly behaviour and their application in the non-covalent synthesis of materials.
It is increasingly apparent that in order to effectively manipulate systems biology, it will be necessary to target protein-protein interactions. What is not clear, is how to effectively target such interfaces with high affinity and selectivity using a small molecule, given that it must cover 800-1100Å of a protein surface and complement the poorly defined projection of hydrophobic and charged domains on a flat or moderately convex surface.
In one approach funded by the EPSRC (EP/C007638/1) we are developing methods for library synthesis of compounds that mimic a-helices. a-Helices are common motifs found at protein-protein interfaces – they project side chain residues in a well defined spatial orientation to achieve binding. Scaffolds that mimic this spatial orientation of binding functionality are therefore attractive inhibitor candidates.
One of our other approaches funded by the EPSRC (EP/F039069 & EP/F038712) and Wellcome Trust (4yr PhD program) concerns recognition of less well-defined protein surfaces – here we are synthesising metal complexes that project binding domains in a variety of spatial orientations suited to recognition of the target protein-surface.
Collaborators: Dr Alison Ashcroft, Dr Thomas Edwards and Dr Stuart Warriner
Small Molecule Probes for Chemical Biology
This is a new area for our group – here we are interested in incorporating synthetic molecules that contain masked reactive intermediates such as diazirines into bio-molecules. Upon excitation with light, diazirines generate highly reactive carbenes which react indiscriminately with proximal functional groups. These compounds therefore have tremendous potential as reagents for tagging and trapping bio-molecules.
Collaborators: Dr Alison Ashcroft and Prof Sheena Radford
Hydrogen-Bond Directed Self-Assembly
In this project funded by EPSRC (EP/D077842/1) we are designing and synthesising small molecules that exhibit well defined self-assembly behaviour. We are also using these compounds as ‘glue’ to construct polymers using non-covalent interactions. This is advantageous because polymers assembled in this manner have stimuli responsive properties.
Collaborators: Huntsman Polyurethanes