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Developing an enzymatic toolbox to make complex modified peptides


Project Description

The pharmaceutical industry has identified a major gap in its portfolio. On the one hand, they are excellent at discovering small molecules that act via a lock and key type mechanism. On the other hand, some diseases are only treatable with biologics such as antibodies and proteins, with associated high costs and difficulties in administering them. The gap between these is filled by large cyclic molecules which behave like small molecule drugs in terms of administration, and behave like biologics in terms of therapeutic effects. However, pharmaceutical industry has no easy way to make such molecules in quantity, nor are there simple ways to modify them.

We have discovered a range of enzymes that allows us to make complex modified linear and cyclic peptides which have high biological activity in a number of human disease states. This process takes a few days, as compared to chemical synthesis which would take months or years.

In this project you will take a hybrid approach to the production of such compounds, using chemical synthesis together with enzymes to create a range of cyclic modified peptides for testing against a number of disease targets. You will gain skills in peptide synthesis, molecular biology, biochemistry and compound separation and identification.

You will work in a supportive group composed of molecular and cell biologists and synthetic and natural product chemists. The research environment for the biological and chemical parts of the project are world class. The biological work will be carried out at the Institute of Medical Sciences, and the chemical work will be carried out at the Marine Biodiscovery Centre.

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.

The successful applicant should have a background in Organic chemistry, Spectroscopy (desirable), Microbiology (desirable), Molecular biology (desirable).

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
• Details of 2 academic referees

Informal inquiries can be made to Professor M Jaspars (@abdn.ac.uk) 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, molecular biology or biotechnology. The successful applicant will be expected to provide the funding for Tuition fees, living expenses and maintenance. Details of the cost of study can be found by visiting View Website. THERE IS NO FUNDING ATTACHED TO THESE PROJECTS. Applicants should also be aware that Additional Research Costs of £600 per annum are required (above Tuition Fees and Living Expenses) for consumables.

References

1. “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

2. “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

3. “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

4. “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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