... understanding life in molecular detail

Prof Andy Wilson

Chemical Biology, Protein-Protein Interactions, Self-Assembly, Synthetic Chemistry


Our multidisciplinary group is interested in the design and synthesis of small/ medium sized molecules that can be used to modulate molecular recognition and self-assembly. Specifially we are focused on (1) developing inhibitors of protein-protein interactions involved in multiple therapeutic areas such as cancer development and progression and (2) the study of amyloidogenic peptides using reactive intermediates and state of the art biophysical techniques.

Current major projects include:
  • Inhibitors of a-helix mediated protein-protein interactions
  • Photocrosslinking of diazirines for structural and mechanistic studies
  • Protein-surface recognition and sensing using ruthenium complexes
  • Synthesis, structural and functional studies of biometic architectures

Our multidisciplinary group is interested in the design and synthesis of small/ medium sized molecules that can be used to modulate molecular recognition and self-assembly.

Specific problems include:

  • Development of small molecules that bind to protein surfaces and inhibit a-helix mediated protein-protein interactions such as the p53/hDM2 and Mcl-1/NOXA B interactions – important cancer targets
  • Development of synthetic agents that can bind to larger less well defined protein surfaces for modulation of protein-protein interactions
  • 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 molecular recognition behaviour and their application in the development of functional biomimetic architectures and non-covalent synthesis of materials.

Protein-surface recognition

Figure 1. A schematic depicting the challenge of protein-protein interaction inhibition using small molecules

In order to effectively intervene in biological processes, it is necessary to inhibit protein-protein interactions (PPIs).1 However, it is difficult to design small molecules that cover 800-1100Å2 of a protein surface and complement the poorly defined projection functional groups on a flat or moderately convex surface (Fig. 1). The research is concerned with the development of scaffolds that posses the required size and shape to cover the large discontiguous projection of functional groups found at protein-protein interfacess. These scaffolds are amenable to rapid modular or dynamic syntheses. We develop both novel aromatic oligoamides as proteomimetics and ruthenium (II) tris-chelates as protein-surface mimetics (Fig. 2).4-5 Current cancer targets include: p53/hDM2, Bcl-xL/BID, Mcl-1/NOXA-B, androgen receptor/co-activator and growth factor/ growth factor receptor interactions. Inhibitors of these targets are being sought to decrease tumour growth, with potential clinical applications in a broad range of cancers, including breast cancer, prostate cancer and small cell lung carcinoma.

Figure 2 (a) Aromatic oligoamide proteomimetics and (b) protein surface mimetics based on ruthenium tris(bipyridine) complexes

A further feature of this program of activity is that the scaffolds we generate often have complex secondary and tertiary structures themselves, so we are also interested in sconforamtional and structural studies of these biometic architectures with a view to understanding how to design complex and functional 3D architectures.

This research area is or has been funded by EPSRC, ERC, YCR and The Wellcome Trust. The research is performed in collaboration with Prof Alison Ashcroft, Prof Alex Breeze, Dr Thomas Edwards, Dr Nick Fletcher (QUB), Dr Andrew Macdonald, Prof Adam Nelson, Prof Sheena Radford, Dr Darren Tomlinson, Dr Stuart Warriner and Prof Adrian Whitehouse.

Small Molecule Probes for Chemical Biology

Figure 3 Schematic depicting how the use of diazirine based photo-activated cross-linkers may be used to obtain structural information on a self-assembled peptide

A key problem in chemical biology is being able to understand biomolecular recognition and self-assembly processes with temporal resolution – this will allow the identification of the transient intermediates that play key roles in signalling, folding and misfolding events. In this research area we incorporate photoactivatable probes (diazirines) into self-assembling peptides and other bioactive ligands which, upon photoexcitation become covalently cross-linked to interacting species by indiscriminate insertion into proximal covalent bonds.

In tandem with non-covalent mass-spectrometry, this allows us to perform detailed structural studies. One of our long term objectives is to use this methodology to move from static to dynamic systems.

This research is or has been funded by EPSRC, BBSRC and ERC. The research is performed in collaboration with Prof Alison Ashcroft, Dr Eric Hewitt and Prof Sheena Radford.

Detailed research programme                  Close ▲
AWil.jpg

Professor or Organic Chemistry and Deputy Director, Astbury
BSc (UMIST) PhD (Warwick)
RSC Norman Heatley Award 2016, Bob Hay Lectureship 2012, EFMC Young Academic Medicinal Chemistry Award (runner-up) 2012, ERC Research Fellow 2010-2015,

Postdoctoral Resaerch Associate (TU/e) 2003
University Research Fellow (Leeds) 2004-2009
Senior Lecturer (Leeds) 2009-2011
Reader (Leeds) 2011-2012

G.15, School of Cemistry
School of Molecular and Cellular Biology
0113 343 1409
a.j.wilson@leeds.ac.uk
http://www.chem.leeds.ac.uk/andrew-wilson/wilson-group.html

Selected Publications

  1. G. M. Burslem, H. F. Kyle, A. L. Breeze, T. A. Edwards, A. S. Nelson, S. L. Warriner, A. J. Wilson*: Towards “Bionic” Proteins: Replacement of Continuous Sequences from HIF-1α with Proteomimetics to Create Functional p300 Binding HIF-1α Mimics, Chem. Commun., 2016, 52, 5421-5424

  2. J. A. Miles, D. J. Yeo, Philip Rowell, S. Rodriguez-Marin, C. M. Pask, S. L. Warriner, T. A. Edwards*, A. J. Wilson*: Hydrocarbon Constrained Peptides – Understanding Preorganization and Binding Affinity, Chem. Sci., 2016, 7, 3694-3702

  3. A. Barnard, K. Long, H. L. Martin, J. A. Miles, T. A. Edwards, D. C. Tomlinson, A. Macdonald,* A. J. Wilson*: Selective and Potent Proteomimetic Inhibitors of Intracellular Protein-Protein Interactions, Angew. Chem. Int. Ed. , 2015, 54, 2960-2965

  4. G. Preston, S. E. Radford, A. E. Ashcroft, A. J. Wilson*: Analysis of Amyloid Nanostructures Using Photo-Crosslinking: In Situ Comparison of Three Widely Used Photo-Crosslinkers, ACS Chem. Biol., 2014, 9, 761–768.