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Downstream Processing and Structure Confirmation of Chemoenzymatically Produced Macrocycles


   Department of Chemistry

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  Prof M Jaspars  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

This project is offered as a collaboration between GyreOx Therapeutics Ltd (www.gyreox.com), the University of Coimbra, Portugal, and the University of Aberdeen. The main PhD work will be carried out at the University of Aberdeen, and there will be a secondment at the company.

Macrocycles, in particular modified cyclic peptides (CPs), are promising compounds that have great potential to hit complex targets in human disease such as protein-protein interactions (PPIs) which are common in diseases such as cancer and inflammation. These targets cannot be modulated using traditional small-molecule chemistry but by using computational design and synthetic and/or enzymatic chemistry processes CPs can be designed and made to inhibit these PPIs. CP production can be carried out in parallel using automation, but there is an industrial need to improve downstream processes to isolate and carry out structure confirmation and provide quality assurance for CPs. The main aim of this project is therefore to use computational and data mining methods on chromatographic and spectroscopic data at each stage of the process to develop tools to predict physicochemical parameters of the CPs to assist their isolation and to automatically confirm their successful synthesis. The objectives are:

1.)       To accurately calculate physicochemical parameters (e.g. logP and PSA) of linear precursors and CPs and use these to optimise compound isolation processes.

2.)       To analyse and understand unique MS fragmentations occurring in linear precursors and CPs and use these to develop a tool to predict the most likely fragmentations.

3.)       To develop a tool that can analyse MS fragmentation data from linear precursors and CPs and compare this to the predicted fragments to confirm successful synthesis.

The student will gain skills in: peptide synthesis and purification; enzyme overexpression and purification; use of enzymes in synthetic steps; HPLC compound purification; use of liquid-chromatography mass spectrometry systems; MS data processing and analysis; MS-MS networking and data presentation; molecular modelling to determine cyclic peptide conformations and physical properties; computer programming to develop cyclic peptide MS analysis tool.

The student will carry out their 3-month placement at GyreOx at its base in Harwell, Oxfordshire, in order to translate the technology developed to the company and apply it to the parallel processes developed by GyreOx. The student will learn how the company operates, take part in compound library generation, downstream processing and analysis.

We are seeking a highly motivated candidate who will hold, or expect to hold, by the time of the project start date, a particularly good UK Honours degree (at least a 2.1 or equivalent) in Chemistry, Biochemistry or Pharmacy.

Knowledge of: Mass spectrometry, Nuclear magnetic resonance spectroscopy, Peptide chemistry. An interest in computer programming and molecular modelling will also be advantageous.

The other supervisors on this project are Dr Bill Primrose, GyreOx Ltd and Dr Bruce Milne, University of Coimbra, Portugal.

APPLICATION PROCEDURE:

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

- Apply for the Degree of Doctor of Philosophy in Chemistry

- State the name of the lead supervisor as the Name of Proposed Supervisor

- State the exact project title on the application form

- All Degree Certificates/Academic Transcripts (officially translated into English and original)

- 2 Academic References on official headed paper and signed or sent from referees official email address

- Detailed CV

We reserve the right to close the advert earlier should a suitable candidate be found before the advertised closing date (Midnight on 22 May 2021). The start date for the project is 1 September 2021 and the student must commence no later than 29 September 2021.


Funding Notes

Applicants must be UK citizens or have settled status in the UK, meaning they have no restrictions on how long they can stay and have been 'ordinarily resident' in the UK for 3 years prior to the start of the studentship.
This 4 year PhD Studentship is part of the IBioIC Collaborative Training Partnership programme http://www.ibioicctp.com/

References

1.) Cyclic Peptides: From Bioorganic Synthesis to Application RSC 2018
2.) Chemistry Open 2017, 6, 11
3.) Nat Chem Biol 2015, 11, 558
4.) Acta Cryst D, 2016, 72, 1174
5.) Nat Struct Mol Biol 2012, 19, 767
6.) Angew Chem 2016, 55, 3596
7.) ChemBioChem 2015, 16, 2646
8.) J Chem Theor Comput 2019, 15, 1652
9.) PCCP 2020, 22, 7169
10.) Angew Chem 2020, 59, 15665 11.) Nat Meth 2009, 6, 596
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