I spoke to Ed Tate recently. Ed was the 2013 winner of the Medimmune Protein & Peptide Science Award and was Plenary speaker at the RSC Protein & Peptide Science Group Early Stage Researcher meeting held in Durham in November 2013 which was sponsored by Cambridge Research Biochemicals.
The Tate group is based in the Department of Chemistry at Imperial College London and their research lies at the interface between organic chemistry, the life sciences and medicine, in the emerging fields of chemical biology and chemical proteomics. The unifying theme of the work is the design and application of novel chemical approaches to understand and manipulate living systems, with an emphasis on processes important to disease. Related to this theme, the group also undertakes research in medicinal chemistry and chemical synthesis/modification of proteins and peptides. So, although not a ‘peptide group’ in the classical sense, peptides and proteins lie at the heart of their work.
Much of the work is focused on post-translational modification of proteins, addressing the questions: What proteins are modified? Where are they modified? Which enzymes modify them? Answers to these questions then lead on to assessing the importance of post-translational modification in disease processes and then identifying targets for intervention. One significant question the group likes to ask is “what are the implications of inhibiting modification?”, i.e. what lies downstream. A major subject of their work is the enzyme N-myristoyl transferase. This enzyme introduces a lipid moiety onto the N-terminus of proteins, usually (but not always) containing N-terminal glycine as an early post-translational modification. They have developed myristic acid derivatives incorporating a C≡C triple bond (alkynylmyristic acid) or azide function (azidomyristic acid) that can be used to introduce tags into N-myristoylated proteins inside living cells. This technique is being used to study protein modification in animal cells and, in particular, protozoan parasites such as Plasmodium, the malaria parasite. The group is developing transferase inhibitors as potential anti-parasite agents, as part of an large collaborative drug discovery programme with groups at Imperial College, Nottingham, York and NIMR.
Other work in the group is aimed at studying protein – protein interactions. Here, peptides are being used to not only study the interaction, but also to develop disruptors of interactions that can be used as the starting point for synthesis of peptide or non-peptide inhibitors with potential therapeutic application.
Like many groups with an interest in peptide and peptide mimetic compounds as starting point for the design and synthesis of drug candidates, the Tate group is using conventional enzyme-targeted approaches (developing inhibitors of key enzymes) as well as more unconventional approaches, such as targeting protein-protein interactions. To do this, they use a range of techniques such as high-throughput library synthesis (peptide arrays and one-bead one-peptide libraries) and screening, through to structure-guided design of conformationally-defined scaffolds.
It was when we started talking about how Ed sees his group’s work developing in the future that we got onto cyclic peptides. Some of the existing work in the group covers the total synthesis of biologically active macromolecules such as the macrocyclic cysteine-knot microproteins (cyclotides). But Ed sees cyclic peptides as being an answer to the much wider problem of how to both lock in to a peptide or peptide mimetic the required conformation for maximum activity as well as increasing bioavailability and reducing degradation. He also feels that cyclic peptides have great potential in cell penetration, either delivering active cargoes or being themselves biologically active.
The work with greatest long-term impact would be aimed at developing a mechanistic understanding of how cyclic peptides penetrate cells, to understand the different conformations that can be adopted and their dynamics. This is likely to arise from the combination of a knowledge-based approach using well-defined structures, and screening approaches that can assay multiple functions in parallel.
An interesting and potentially enormously valuable aspect of cyclic peptides would be the discovery and development of scaffolds that can cross an intact blood brain barrier (BBB). Part of their work focusses on defined scaffolds that can present combinations of ligands in well-characterised orientations; some might interact with specific protein transport receptors, mediating transport across the BBB, while other ligands might carry bioactive cargoes or interact with drug target receptors in the CNS. However, it is not an easy field of study; in vivo models are difficult, as are cell based assays, so the biology is difficult in addition to the chemistry. But it is a worthwhile challenge! Their current work is focused on autism and the role of oxytocin, however, the methods they are developing should have general application.
It is also clear that the field of cyclic peptides is not without its problems. For example, the cyclic pentapeptide Cilengitide recently suffered a major setback in Phase III trials for treatment of glioblastoma, where it showed no increased survival compared to established treatments. The drug may not now be progressed further by Merck KGaA – this represents a significant cost to the company, coming at a very late (and expensive) stage in development. Cilengitide competes for the RGD sequence that regulates integrin-ligand binding and at higher concentrations inhibits angiogenesis in vitro – this was the rationale for its use as an anti-cancer drug, but it appears that this reasoning may have been based on an incomplete understanding of the influence of fluctuating peptide levels on angiogenesis. Nevertheless, this failing was not inherent to the cyclic peptide nature of the drug, and there is still everything to play for in the brave new world of cyclic peptide therapeutics – the next decade should be a very exciting time for the field.
Stephen Hoare, Owner / Principal at Peptide Conferences