Steven Cobb was introduced to peptide chemistry through working as a post-doc with Professor John Vederas, University of Alberta. After that he moved to the Department of Chemistry in the University of Durham in 2007 and was appointed Lecturer in 2010. The research in the Cobb group is quite wide and varied, covering the whole range of amino-acid, peptide and protein research. They are involved in the synthesis of non-natural amino acids, bioactive dipeptides (inhibitors of chemokine induced chemotaxis) right up to synthesis of large peptides and proteins.
The group is also working on peptide biomaterials by linking peptides to carbon nanotubes utilising novel amino acids made in the group; this work is done in collaboration with Prof. Karl Coleman who also works in the Department of Chemistry at Durham. The Cobb group’s novel amino acids are also used in the preparation of light activated peptide drug delivery systems in collaboration with Dr Ka-La Wong (Hong Kong Baptist University) – this work has been published recently.
I visited Steven recently to discuss the projects he has running in collaboration with Cambridge Research Biochemicals (CRB). I wanted to learn more about his research, but particularly to find out what benefit he had obtained from the collaboration and what was most useful to him and his research from the relationship.
The first thing I realised was that this was not a one-way relationship. Steven had a masters student about 4 or 5 years previously who was then employed by Cambridge Research Biochemicals (CRB) because he was good at making peptides!
The collaboration with Cambridge Research Biochemicals (CRB) is based around the group’s work on chemokines, in particular CCL2. There are two strands to this work, one of which is ‘traditional’ medicinal chemistry.
CCL2 induces chemotaxis that results in inflammation that damages heart tissue following cardiac bypass. A suitable CCL2 inhibitor might be an appropriate treatment for the shock response that can result when a patient is taken off bypass. The lead compound is a naturally-occurring diketopiperazine (DKP) consisting of a dichlorotyrosine and a proline. The DKP is specific for CCL2, unlike other inhibitors, and as a DKP it is relatively robust which makes it a good lead compound. The group is currently working to increase its potency as an inhibitor by preparing DKPs with different proline analogues and different tyrosine analogues. The work is being done in collaboration with Dr Ehmke Pohl (Durham, Protein Crystallography) and Professors Simi Ali and John Kirby (Newcastle University, Medical School).
Steven has had a 1 year Knowledge Transfer Partnership student (a joint project between Newcastle, Durham and CRB) working on aspects of this project. They are now building a library (currently 20 compounds) of DKPs made using a safety-catch linker to cyclise.
In parallel to this work, the group is also developing synthetic routes to CCL2 and analogues. Because of the size of the targets they are preparing fragments for assembly by native chemical ligation (NCL). This allows them to incorporate various amino acid probes that they have prepared to use as reporters in binding studies, using for example isothermal titration calorimety to elucidate modes of action and to probe the protein-protein interactions that underpin the dimerisation of CCL2 that occurs prior to receptor binding. An early target was CCL2s that are nitrated on specific tyrosines – nitration of the native molecule is non-specific, so this allows identification of the essential tyrosines. The other objective is to make CCL2 analogues that are not commercially available. A lot of this work is being done by an EPSRC-funded CASE student; these particular awards are designed to bring together universities and Small & Medium Enterprises (SMEs) in the North East of England – so CRB was an ideal fit.
I was surprised at the answer to my question “what do you get out of your collaboration with Cambridge Research Biochemicals?” I thought it might be something prosaic like “money” or “brownie points with the university”, but actually it was better than that. Steven said that it was the fact that, because the comapny made many more peptides than an academic lab such as his ever would, they were always a source of useful practical advice about peptide synthesis and purification. Also, being an SME there were just a small number of key people who were there throughout, rather than dealing with the changing personnel that you get in a large organisation. So their regular meetings had continuity and purpose. Also, if something needed action, decisions could be taken quickly and effectively.
Stephen Hoare, Owner / Principal at Peptide Conferences