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EastBio Expanding enzymatic fluorination: development of artificial fluorinases


Project Description

Fluorine is an important element in drug design, as it can be used to both increase the half-life of a drug and its bioavailability. Today, 20% of the pharmaceuticals on the market contain fluorine, and 18F labelled molecules can be used for PET imaging in disease diagnosis. Therefore, a number of synthetic methods have been generated to make C-F bonds, including catalytic C-H fluorination. In nature, fluorine is introduced into molecules using SAM-dependant fluorinases.1 Unlike other halogenases only one native fluorinase is known and almost all known fluorometabolites are made via 5’-fluoro-5’-deoxyadenosine, thus limiting the position where fluorine can be introduced. In comparison, synthetic chemistry has numerous methods to introduce fluorine into different molecules both at an early and late stage in the molecule synthesis. However, complete control of selectivity is often hard control chemically compared to enzymatic synthesis.

Artificial enzymes provide a method of introducing highly selective new-to-nature reactions into the biocatalytic toolbox.2. In this project, we will look to introduce metal cofactors that are known to catalyse C-H fluorination reactions into proteins scaffolds to obtain artificial metalloenzymes for selective fluorination reactions. The catalysts will be applied in the late-stage modification of bioactive molecules, to improve their biological properties.

Training will be provided in molecular biology (i.e. the growth, expression and purification of proteins, and subsequent genetic optimisation via either site-directed or random mutagenesis), structural biology and bioinorganic chemistry (understanding metal binding of the proteins using methods such as NMR, UV-vis, crystallography), and in the organic chemistry needed for catalytic testing (both synthesis and analysis i.e. HPLC, GC). This project will particularly suit students who are interested in the chemical/biological interface.

Application Process:
To apply for an EASTBIO PhD studentship, follow the instructions below:
1) Check FindaPhD for our available projects and contact Dr Amanda Jarvis before you apply. Please note that the majority of our projects will go live in the w/b 4 November.

2) After you have discussed the projects of interest to you with the project supervisors, download and complete our Equality, Diversity and Inclusion survey and then fill in the EASTBIO Application Form and submit to each of your proposed projects as per the instructions in the project adverts.

3) Send the EASTBIO Reference Form to your two academic/professional referees, and ask them to submit as specified on the project adverts.

4) If you are nominated by the supervisor(s) of the EASTBIO PhD project you wish to apply for, they will provide a Supervisor Support Statement.

5) We anticipate that our first set of interviews will be in the week commencing 10th February 2020 with awards made the following week.

If you have further queries about the application/recruitment process please email EastBio.
Please ask your referees to submit your references directly to Dr Amanda Jarvis

The School of Chemistry holds a Silver Athena SWAN award in recognition of our commitment to advance gender equality in higher education. The University is a member of the Race Equality Charter and is a Stonewall Scotland Diversity Champion, actively promoting LGBT equality. The University has a range of initiatives to support a family friendly working environment. See our University Initiatives website for further information. University Initiatives website: https://www.ed.ac.uk/equality-diversity/help-advice/family-friendly

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral 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.

References

1. D. O’Hagan and H. Deng, Enzymatic Fluorination and Biotechnological Developments, Chem. Rev. 2015, 115, 634.
2. A. G. Jarvis et al. Enzyme activity by design: an artificial rhodium hydroformylase for linear aldehydes, Angew. Chem., Int. Ed. 2017, 56, 13596.

How good is research at University of Edinburgh in Chemistry?
(joint submission with University of St Andrews)

FTE Category A staff submitted: 43.30

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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