Supervisor: Prof. G J Langley, Dr E Stulz, Dr A Ray (AstraZeneca), Dr S Holman (AstraZeneca)
Oligonucleotides are a promising and growing class of therapeutics. There are currently ~10 oligonucleotide drugs on the market, and many more presently in clinical trials. Many of these therapeutic oligonucleotides feature modifications which are designed to protect against degradation or enhance their activity. Conjugation of oligonucleotides has also been used to modulate protein binding and tissue distribution. This analytical PhD project, a collaboration between a world-class mass spectrometry research group and a world-leading pharmaceutical company, will seek to understand the characterisation of these revolutionary drugs.
Mass spectrometry is a key analytical technique used to characterise and structurally elucidate molecules in drug discovery and development using tandem mass spectrometry (MS/MS). This process is underpinned by an understanding of the gas-phase chemistry of the molecules under investigation to interpret the fragment ions formed and relate them back to the original structure.
At present, a deep understanding of the gas-phase ion fragmentation behaviour of therapeutic oligonucleotides is lacking, hampering efforts to characterise them and slowing their journey to market. To address these deficiencies in understanding, this PhD project will seek to investigate the impact of pharmaceutically-relevant modifications on the MS/MS behaviour and gas-phase stability of the oligonucleotides. This will allow mechanisms for the different fragmentation processes to be probed and developed. Using the increased understanding of the ion dissociation pathways, databases of structures and fragmentation trees will be built, hierarchical structural drivers of fragmentation proposed, and protocols for the interpretation of modified oligonucleotides developed. The student will gain experience in a number of fragmentation techniques (CID, HCD, ETD) and different mass analysers, including QToF, FT-ICR and Orbitrap technologies.
This EPSRC CASE Conversion project will be in collaboration with AstraZeneca, and the successful student will have opportunity to undertake a three-month placement at the company’s Macclesfield Research & Development site during the PhD, providing valuable industrial experience. As part of this placement, the student will have access to additional instrumentation not available at Southampton, and will assess the transferability of their findings with the mass spectrometry teams at AstraZeneca in both Macclesfield and Gothenburg. Further, ad hoc visits as required by the progress of the research will be undertaken. The student will also attend AstraZeneca’s PhD Day to present their work, as well as be expected to present posters and orals at international conferences.
This project is well-suited to those with strong skills and a keen interest in analytical chemistry, and its application to the pharmaceutical industry. An interest in physical-organic chemistry is desirable.
A very good undergraduate degree (at least a UK 2:1 honours degree, or its international equivalent).
Closing date: 01 July 2020
Funding: full tuition fees for EU/UK students plus for UK students, an enhanced stipend of £15,285 tax-free per annum for up to 3.5 years.
How To Apply
Applications should be made online, please select the academic session 2020-21 “PhD Chemistry (Full time)” as the programme. Please enter John Langley under the proposed supervisor.
Applications should include:
Two reference letters
Degree Transcripts to date
Apply online: https://www.southampton.ac.uk/courses/how-to-apply/postgraduate-applications.page
For further information please contact: [email protected]