... understanding life in molecular detail

Dr Robin Bon

Chemical Biology, Medicinal Chemistry


We are interested in the development of chemical tools for the study of biological phenomena. Such chemical tools will be used for the perturbation of protein function in cells or disease models, for the profiling of protein activity in biological samples, or for the visualisation of proteins in vivo.

Current major projects include:
  • Chemical tools for the study of ion channels
  • Peptide reporters of protein activities and interactions
  • Modified proteins as targeted contrast agents for MRI
  • Modified surfaces for biosensing and imaging

Project 1. Detection of enzymatic activity by electrochemical spectroscopy

James Murray, Dr. Dominika Nowak, Mathieu Guillorit, Sjors van Klaveren, in collaboration with Dr. Steven Johnson at York and Dr. Kevin Critchley at Leeds; Funding: EPSRC

The sequencing of the human genome has provided a wealth of valuable information regarding the genetic basis of disease. However, a comprehensive understanding of cellular function, in both healthy and diseased cells, requires knowledge not only of the genome but also a thorough catalogue of protein expression, protein interactions and protein function. While protein concentration can be profiled directly via proteomic techniques, protein function is determined by the specific three-dimensional protein structure that is regulated precisely through, for example, post-translational modification (PTM) or by interactions with other molecules. In order to measure functional differences in living systems we have to reach beyond conventional genomics and proteomics approaches, and develop novel techniques that can interrogate protein function. This project integrates synthetic chemistry with electronic engineering in order to demonstrate label-free interrogation of enzymatic activity. The concept of the project is illustrated in Figure 1.

Figure 1. Electrochemical detection of enzymatic activity. Substrates are chemoselectively immobilised on electrodes via self-assembled monolayers (SAMs). Upon enzymatic processing, the change of their size, charge, or redox behaviour is measured using electrochemical spectroscopy.

We have recently developed a solid phase synthesis of functionalised alkanethiol-PEGs for incorporation in SAMs (and functionalisation of nanoparticles). We are currently studying their application in the site-selective immobilisation of peptides and proteins, and the detection of biomolecular interactions on the functionalised SAMs by a range of electrochemical and biophysical techniques such as CV, EIS, MALDI, and SPR.

 

Project 2. Design and synthesis of selective TRPC5 inhibitors

Anet Varghese, Dimitrios Poulcharidis, Jason Gresly, William Evans, James Holt-Martyn, Katherine Brodie, Mladen Stojanovic, with Prof. David Beech at Leeds

TRPC function is implicated in cardiovascular remodelling and inflammation. Therefore, TRPC modulation may have a positive effect on diseases caused by these processes, such as atherosclerosis and abdominal aortic aneurisms. However, the biology and pharmacology of TRPC channels is currently insufficiently understood to consider them validated drug targets. In addition, because TRPC function is measured in whole cells, the molecular targets of most TRPC modulators are currently unknown and probably diverse. Potent and selective modulators of the 7 different TRPC channels would provide valuable fundamental insights into TRPC channel biology and pathophysiology. Furthermore, identification of the molecular targets of TRPC modulators would lead to either the validation of TRPC channels as druggable proteins or the identification of their regulator proteins (either known or newly identified) as druggable potential targets for TRPC modulation. Several small molecule modulators of the canonical transient receptor potential (TRPC) channels have recently been discovered at Leeds, which has led us to propose a new TRPC pharmacophore (Amer et al., British Journal of Pharmacology 2013, 1445–1455). We are currently optimising the original hits and trying to identify their cellular targets using covalent target identification probes.

 

Project 3. Modular synthesis of targeted MR contrast agents

Dr. Martin Fisher, in collaboration with Dr. Azhar Maqbool, Prof. Sven Plein, Dr. Iain Manfield, Dr. Justin Ainscough, and Dr. Richard Foster at Leeds; Funding: British Heart Foundation

Gadolinium (Gd) chelates are widely applied as contrast agents in magnetic resonance imaging (MRI). The development of hybrids of Gd chelates and ligands of proteins such as collagen and elastin has enabled the imaging of tissues that are enriched with these proteins. In this project we aim for the establishment of a chemical toolbox containing building blocks (Gd chelates, linkers, targeting moieties) for the modular synthesis of targeted Gd contrast agents, and to apply these novel contrast agents to answer questions in basic and clinical cardiac science.

Detailed research programme                  Close ▲
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Lecturer in Cardiovascular Chemistry
BSc PhD (Amsterdam)
Thieme Chemistry Journal Award 2012, Alexander von Humboldt Fellowship 2007-2009, Prof. Dr. H.J. Backer Prize 2007

Senior Translational Research Fellow (University of Leeds) 2009-2015
Postdoctoral Research Fellow (Max Planck Institute) 2006-2009


LIGHT building, level 7
School of Biomedical Sciences
01133437744
r.bon@leeds.ac.uk

Selected Publications

  1. Naylor, J.; Minard, A.; Gaunt, H.J.; Amer, Wilson, L.A.; M.S.; Migliore, M.; Cheung, S.Y.; Rubaiy, H.N.; Blythe, N.M.; Musialowski, K.E.; Ludlow, M.J.; Evans, W.D.; Green, B.L.; Yang, H; You, Y.; Li, J.; Fishwick, C.W.G.; Muraki, K.; Beech, D.J.; Bon, R.S. ‘Natural and synthetic flavonoid modulation of TRPC5 channels’. British Journal of Pharmacology 2016, 173, 562–574.

  2. Fisher, M.J.; Williamson, D.J.; Burslem, G.M.; Plante, J.P.; Manfield, I.W.; Tiede, C.; Ault, J.R.; Stockley, P.G.; Plein, S.; Maqbool, A.; Tomlinson, D.C.; Foster, R.; Warriner, S.L.; Bon, R.S. ‘Trivalent Gd-DOTA reagents for modification of proteins’ RSC Advances 2015, 5, 96194–96200.

  3. Murray, J.; Nowak, D.; Pukenas, L.; Azhar, R.; Guillorit, M.; Wälti, C.; Critchley, K.; Johnson, S.; Bon, R.S. ‘Solid phase synthesis of functionalised SAM-forming alkanethiol–oligoethyleneglycols’ Journal of Materials Chemistry B 2014, 2, 3741–3744

  4. Bon, R.S.; Beech, D.J. ‘In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels – mirage or pot of gold?’ British Journal of Pharmacology 2013, 170, 459–474