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Beyond Making Thiazolines and Oxazolines: Expanding the Enzymatic Repertoire to incorporate other 5- and 6-membered heterocyclic rings in peptides


Project Description

Cyclic peptides have a great therapeutic potential with several examples reach the clinic e.g. gramicidin S (antibiotic), ziconotide (pain relief), somatostatin (anticancer) and cyclosporine (immunosuppressant) and many others are in the late stages of clinical trials e.g. plitidepsin (anticancer). Several modifications are usually made to these compounds in order to enhance their cellular permeability and improve their receptor binding affinity and ADME properties. Among these modifications is the incorporation of heterocyclic rings. Heterocyclic rings are well-represented in many drugs e.g. the chemotherapeutic agent ixabepilone and the antiprotozoal agent metronidazole. Chemical methods to generate heterocycles in peptides are expensive, challenging, time consuming and produce toxic waste. In our group, we engineer biosynthetic enzymes from the ribosomally synthesized and post-translationally modified peptides (RiPPs) pathways and recruit these to make modifications to peptide substrates.1

Our set of enzymes includes heterocyclases forming thiazoline and oxazoline, macrocyclases, thiazoline oxidases and prenylases. This project aims to expand our enzymatic repertoire with new enzymes that can generate heterocycles other than thiazoline and oxazoline.
The proposed work will benefit from the exponential growth in characterisation of natural-product biosynthetic machineries in the past two decades. We will first focus on the rapidly growing class of RiPPs. These enzymes process a ribosomally-encoded precursor peptide containing the sequence that will be processed into the natural product and a leader sequence that contains the recognition determinants by the processing enzymes. The plasticity and the small number of enzymes involved in each pathway allow access to great chemical diversity at low genetic cost. The compounds produced as well as their unmodified counterparts will be tested in relevant biological screens.

The project is cross‐disciplinary, involving elements of molecular biology, chemical biology and synthetic peptide chemistry. You will gain experience in solid phase peptide synthesis, genome mining, cloning, site directed mutagenesis, codon reprogramming, protein expression and purification as well as using the purified enzymes to carry out reactions on synthetic substrates. You will learn how to measure catalytic rates of the heterocyclases using biochemical techniques and LC‐MS analyses. As part of the training, you will spend one year at Ingenza Ltd. to learn scalable fed-batch fermentation, combinatorial genetic assembly and protein expression in yeast. This is in addition to three mandatory training sessions per year provided by IBioIC.

APPLICATION PROCEDURE:
Please apply for admission to the ’Degree of Doctor of Philosophy in Medical Sciences’ to ensure that your application is passed to the correct school for processing. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php.

Funding Notes

This studentship is fully funded for four years through IBioIC Collaborative Training Partnership (View Website).

This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

References

1- Houssen et al. (2014) Angew. Chem. Int. Ed. 53, 14171-14174.

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