PhD Studentship - Design, Synthesis and Evaluation of Next Generation Nucleoside and Nucleotide Analogues

Research theme: Organic and Biological Chemistry

How to apply: uom.link/pgr-apply-2425

UK students

This 4-year PhD studentship is open to Home (UK) applicants. The successful candidate will receive an annual tax-free stipend set at the UKRI rate (£20,780 for 2025/26; subject to annual uplift), and tuition fees will be paid. We expect the stipend to increase each year. The start date is October 2026.

We recommend that you apply early as the advert will be removed once the position has been filled.

Canonical nucleosides constitute the building blocks for the biomolecules of life. They are integral components of oligonucleotides (DNA and RNA) that encode the proteins required to control biological processes. Nucleosides are also omnipresent within enzyme cofactors (NAD+/H), as cellular energy sources (ATP) and as secondary signaling molecules (cyclic dinucleotides). Synthetic analogues of nucleosides, nucleotides, and oligonucleotides represent a successful strategy to develop therapeutics that target diverse biological processes. These include DNA replication, transcription, translation and cell signaling. To exemplify, nucleoside analogues possess an accomplished history within therapeutic intervention strategies, most notably against viruses (e.g., Entecavir, Sofosbuvir) and cancer (e.g., Clofarabine, Forodesine)[1,2] and recently as frontline treatments against COVID-19 (Remdesivir, Molnupiravir).[3,4] Relatedly, cyclic dinucleotides are secondary signaling molecules comprised of two phosphodiester-linked nucleotide components which control many processes in both prokaryotes and eukaryotes. They activate the stimulator of interferon genes (STING) protein to elicit an immune response and are currently being evaluated as potential cancer treatments.[5] Broadly, these nucleoside and nucleotide analogues target proteins to exert their therapeutic effect. Comparatively, oligonucleotide (or nucleic acid) therapeutics commonly target mRNA to perturb the production of disease-related proteins.[6] Oligonucleotide therapeutics are an emergent drug modality and consist of modified or unmodified short nucleic acid sequences; these include antisense oligonucleotides (ASOs), small interfering RNA (siRNAs), microRNA (miRNAs), aptamers, and DNAzymes.[7] Notable also from recent times is the use of oligonucleotide sequences (mRNA) in the development of a vaccine for SARS CoV 2.
To meet a growing demand for next generation small molecule and RNA-based therapeutics, novel nucleoside analogue scaffolds are required. This is complimented by the need to develop more efficient, sustainable and cost-effective synthetic methods to produce them. Building upon the group’s prior work in this area (millerresearchgroup.co.uk),[8-14] this PhD will involve the design and chemoenzymatic synthesis of a new nucleoside and nucleotide analogues to enable their evaluation in relevant biological systems. You will receive training in organic synthesis, carbohydrate chemistry, chemoenzymatic synthesis and molecular microbiology, all geared towards the design and development of routes to novel nucleoside/nucleotide targets. Transferable skills such as reporting of results orally and in writing, time management, project planning and management will also be developed.

Applicants should have, or expect to achieve, at least a 2.1 honours degree or a master’s (or international equivalent) in a relevant science or engineering related discipline.

To apply, please contact the supervisors; Prof Gavin Miller - gavin.miller@manchester.ac.uk and Dr Lovelock - sarah.lovelock@manchester.ac.uk. Please include details of your current level of study, academic background and any relevant experience and include a paragraph about your motivation to study this PhD project.

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