This iCASE BBSRC PhD studentship is a collaboration between Professor Alethea Tabor’s group at UCL and Cambridge Research Biochemicals (CRB): https://www.ucl.ac.uk/chemistry/people/professor-alethea-b-tabor https://www.crbdiscovery.com/
The aim of this project is to develop a range of bioactive cyclic peptides incorporating the unusual amino acids lanthionine and cystathionine as metabolically stable, non-reducible replacements for disulfide linkages. The student will develop solid-phase synthesis approaches to these peptides and will study their conformational properties by NMR.
Cyclic peptides frequently show highly potent and selective binding to therapeutically relevant targets, such as receptors, protein-protein interactions (PPI) and transcription factors. These targets are difficult to address with small molecule therapeutics or with biologics. The conventional approach to applying a conformational constraint to a peptide lead is to cyclise the peptide by introducing a disulfide bridge between two Cys residues. However, such linkages are reduced in vivo and are not metabolically stable; thus there is considerable interest in making cyclic peptides which have a thioether linkage (from incorporation of lanthionine or cystathionine) instead. CRB are frequently asked by their clients to provide cyclic peptide analogues containing these unnatural linkages as tools and probes for early stage drug discovery programmes.
The Tabor group have pioneered a solid-phase peptide synthesis (SPPS) approach to lanthionine-containing peptides [1,2,3]. This involves the stereoselective synthesis of orthogonally protected lanthonine, the incorporation of this residue in a linear peptide, selective removal of one set of protecting groups, cyclisation on-resin and chain extension. This is now the method used by groups worldwide for the chemical synthesis of lantibiotics, an emerging class of antimicrobial peptides. However, this method has not yet been widely used to prepare non-reducible, conformationally constrained analogues of other biologically active peptides, nor of incorporating cystathionine. The effects of introducing thioether bridges on the conformation and biological properties of these peptides is also not well understood. This project will therefore focus on applying the SPPS approach to synthesising thioether bridged conformationally constrained analogues of key peptides involved in receptor binding. The student will initially work in the UCL laboratories, learning and further developing the organic synthesis and solid phase peptide synthesis techniques required, and will synthesise thioether bridged analogues of known biologically active peptides as proof of principle. During the PhD there will be two placements at CRB, where the student will have access to facilities for scaling up the synthesis of the required amino acids, and will work on client-related cyclic peptide projects.
In order to understand the effect that these disulphide bond replacements have on the peptide conformation, and in particular to determine whether the peptides can adopt the biologically active conformation, the structural properties of these peptides will be analysed by NMR. For this, the student will use the technique of NAMFIS analysis , in collaboration with Professor Mate Erdelyi (University of Uppsala). The student will also spend 3 – 4 months on placement in Uppsala, receiving training in this technique: http://halogenbond.weebly.com/
Our goal is to make lanthionine- and cystathionine-bridged peptides widely available as probes and tools for research in academia and in pharmaceutical and biotechnology companies. This collaboration between academic groups at UCL and Uppsala, and a leading biotechnology SME, will provide an excellent training for the PhD student as well as developing new peptide tools for biological research.
Applications must be complete, including references, by 11th January 2018 at 5pm
1. Bregant, S., Tabor, A. B. J Org Chem 70, 2430 (2005)
2. Mothia, B. et al Org Lett 13, 4216 (2011)
3. Wright, Z. V. F. et al J Am Chem Soc 139, 13063 (2017)
4. Danelius, E. et al Biochemistry 56, 3265 (2017)