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In Silico design and chemoenzymatic synthesis of bioactive cyclic and stapled peptides

Project Description

Cyclic and modified cyclic peptides are very appealing scaffolds especially as therapeutics 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). They can modulate very challenging therapeutic targets such as protein-protein interactions (PPIs) which are involved in many difficult-to-treat diseases e.g. immune disorders, psoriasis and cancer. Large molecular weight biological drugs e.g. antibodies can also disrupt PPIs but are very expensive and only available as injections. Cyclic peptides, on the contrary, are much cheaper, can be administered via different routes and can be formulated to produce a local rather than systemic effect. Compared to their linear counterparts, cyclic peptides are more stable to metabolic degradation, have better target binding affinity and are more capable to cross cellular membranes and reach intracellular targets. However, synthesis of cyclic peptides is very challenging. Cyclosporine, for example, is produced by microbial fermentation because chemical synthesis is not economically viable. Modifications to these scaffolds are also very critical to improve the therapeutic index, tune ADME properties or to enhance membrane permeability.

In our group we use engineered biosynthetic enzymes to carry out some challenging chemical transformations. Our set of enzymes includes heterocyclases forming thiazoline and oxazoline, macrocyclases, thiazoline oxidases and prenylases. Although these enzymes allow access to a wide range of what is previously considered synthetically-challenging compounds, they have some limitations mainly with regard to ring size and the modifications that can be implemented.

This studentship aims at:
1- Recruitment of new biosynthetic enzymes that can modify peptides.
2- In silico design of novel cyclic and stapled peptides against specific therapeutic targets.
3- Chemoenzymatic synthesis of the peptides designed in 2.
4- Biological testing of the generated peptides.

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 ribosomal peptide synthetases (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.

You will gain skills in genome mining, protein expression and purification, biochemical characterisation of enzymes, in silico drug design, solid phase peptide synthesis, structure elucidation using spectroscopic methods and in vitro biological testing.

Application Procedure:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. 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.

Funding Notes

Full funding for 3 years is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

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.

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