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Toward developing next-generation therapeutics - targeting the undruggable interactome


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. Our group, in collaboration with Naismith group, has developed a novel method to produce bioactive azole-containing cyclic peptides. The new method recruits engineered marine-derived biosynthetic enzymes to carry out the difficult 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 proposal aims at expanding our enzymatic toolbox to explore a wider chemical space by introducing a variety of chemical modifications e.g. N-methylation (to increase cellular permeability), chlorination and fluorination, glycosylation and incorporation of 6-membered heterocycles and fatty acid chains. 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 for their ability to inhibit cancer related key protein-protein interactions.

You will gain skills in in silico drug design, solid phase peptide synthesis, molecular biology, biochemistry and spectroscopic identification of compound structures.

Candidates should have (or expect to achieve) a UK honours degree at 2.1 or above (or equivalent) in Chemistry, biochemistry, cell & molecular biology, pharmacy.

APPLICATION PROCEDURE:

• Apply for Degree of Doctor of Philosophy in Chemistry
• State name of the lead supervisor as the Name of Proposed Supervisor
• State ‘Self-funded’ as Intended Source of Funding
• State the exact project title on the application form

When applying please ensure all required documents are attached:

• All degree certificates and transcripts (Undergraduate AND Postgraduate MSc-officially translated into English where necessary)
• Detailed CV

Informal inquiries can be made to Dr W Houssen () with a copy of your curriculum vitae and cover letter. All general enquiries should be directed to the Postgraduate Research School ()

Funding Notes

This project is advertised in relation to the research areas of the discipline of Chemistry. The successful applicant will be expected to provide the funding for Tuition fees, living expenses and maintenance along with Additional Research Costs of £6,000 per annum. Details of the cost of study can be found by visiting View Website. THERE IS NO FUNDING ATTACHED TO THIS PROJECT.

References

1- “N-prenylation of tryptophan by an aromatic prenyltransferase from the cyanobactin biosynthetic pathway” L. Dalponte, A. Parajuli, E. Younger, A. Mattila, J. Jokela, M. Wahlsten, N. Leikoski, S. A. Jarmusch, K. Sivonen, W. E. Houssen, D. P. Fewer. Biochemistry 2018, 57, 6860.
2- “Cyclic Peptide Production Using a Macrocyclase with Enhanced Substrate Promiscuity and Relaxed Recognition Determinants” Cristina N. Alexandru-Crivac, Christian Umeobika, Niina Leikoski, Jouni Jokela, Kirstie Rickaby, André M. Grilo, Peter Sjö, Alleyn T. Plowright, Mohannad Idress, Eike Siebs, Ada Nneoyi-Egbe, Matti Wahlsten, Kaarina Sivonen, Marcel Jaspars, Laurent Trembleau, David P. Fewer and Wael E. Houssen. Chem Comm 2017, 53, 10656
3- “A Unique Tryptophan C-Prenyltransferase from the Kawaguchipeptin Biosynthetic Pathway” Anirudra Parajuli, Daniel H. Kwak, Luca Dalponte, Niina Leikoski, Tomas Galica, Ugochukwu Umeobika, Laurent Trembleau, Andrew Bent, Kaarina Sivonen, Matti Wahlsten, Hao Wang, Ermanno Rizzi, Gianluca De Bellis, James Naismith, Marcel Jaspars, Xinyu Liu, Wael Houssen, and David P. Fewer, Angew. Chem. Int. Ed. 2016, 55, 3596
4- “Structural Analysis of Leader Peptide Binding Enables Leader-Free Cyanobactin Processing” Jesko Koehnke, Greg Mann, Andrew F Bent, Hannes Ludewig, Sally Shirran, Catherine Botting, Tomas Lebl, Wael E Houssen, Marcel Jaspars, & James H Naismith Nat Chem Biol 2015, 11, 558
5- “An Efficient Method for the In Vitro Production of Azoline-Based Cyclic Peptides.” Wael E. Houssen, Andrew F. Bent, Andrew R. McEwan, Nathalie Pieiller, Jioji Tabudravu, Jesko Koehnke, Greg Mann, Rosemary I. Adaba, Louise Thomas, Usama W. Hawas, Huanting Liu, Ulrich Schwarz-Linek, Margaret C. M. Smith, James H. Naismith, Marcel Jaspars, Angew. Chem. Int. Ed. 2014, 53 14171

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