Novel photochemical approaches to the synthesis of multicyclic peptides: Chemical tools to probe the role of protein-protein interactions in cancer and muscle wasting

Key words: synthetic organic chemistry; peptide chemistry; photochemistry; chemical biology/medicinal chemistry

Protein-protein interactions (PPIs), when two proteins physically interact, are key effectors of cellular signaling, and play a role in almost all healthy physiological processes. Aberrant expression or mutation of one or more protein partners is linked with a wide range of diseases. Small molecule approaches to treat disease are generally ineffective as PPI inhibitors. As such, access to new ‘chemical space’ is urgently required. Peptides, including macrocyclic and stapled peptides, have emerged as effective PPI modulators due to the presentation of native-like amino acid motifs with ability to mimic a protein surface at the PPI interface.

The Coxon Group (School of Pharmacy and Biomolecular Sciences) have developed methods for the chemoselective functionalisation of peptide side chains with perfluoro-heteroaromatic reagents and have applied this to the preparation of designed stapled peptides as inhibitors of protein-protein interactions. We will expand on this established research programme and introduce novel photochemical methods (with Dr Lu Shin Wong, Manchester University) to explore the preparation of cyclic, multicyclic and stapled peptide systems that can mimic a native protein. These methods will expedite access to novel chemical scaffolds for drug discovery.

These will be tested in relevant murine and human cell culture systems with Dr. Adam Sharples and Prof. Claire Stewart (Stem Cell, Ageing and Molecular Research, School of Sports and Exercise Science, Life Sciences Building).

This project will involve aspects of: i) synthetic organic chemistry; ii) peptide chemistry; ii) photochemistry; iv) chemical biology/medicinal chemistry; v) molecular and cell biology. Training in each of these areas will be provided as part of the research programme.

The successful applicant will be located in brand new research laboratories on our Byrom Street campus. Following the successful completion of the Life Sciences Building refurbishment programme to build a bespoke research focused life sciences building in 2013 (investment of £8M for infrastructure, £1M additional equipment); LJMU have also recently invested £12M to fully refurbish the chemistry research laboratories in the James Parsons Building. This has delivered a modern and state of the art research facility, which will include the acquisition of a dedicated 600 MHz NMR, a new QToF mass spectrometer and the purchase of an automated microwave-assisted peptide synthesiser.

The University have continued to invest heavily in new staff and student facilities, including the recently opened Byrom Street Social Zone.

For more information:
• RISES: 2nd highest ranked institution in the UK for research in sport and exercise sciences (0.01 marks off the top 1st position).
• 11th best academic department in the country (out of 1,911 submissions).
• Top ranked department in all post-92 institutions.
• 97% of our research activity rated world-leading or internationally excellent.

All Candidates must satisfy the University’s minimum doctoral entry criteria for studentships of an honours degree at upper second class (2:1) or an appropriate Master’s degree or equivalent in Chemistry. A minimum IELTS score of 7 (or equivalent) is essential for candidates for whom English is not their first language. This fully-funded studentship is open to both UK/EU students.

Applications (including a CV and cover letter) should be made directly to Dr Christopher R. Coxon (email: [Email Address Removed]; telephone: 0151 904 6344). Dr Coxon can also be contacted for further information.