PhD Studentship: (BioProcess) Harnessing Biocatalysis Toward Next Generation Nucleoside Triphopshates

Department: Chemistry
Title: (BioProcess) Harnessing Biocatalysis Toward Next Generation Nucleoside Triphopshates
Application deadline: All year round
How to apply: Click the 'Apply' button above.

UK only

This 4-year PhD project is fully funded and home students, are eligible to apply. The successful candidate will receive an annual tax-free stipend set at the UKRI rate (£20,780 for 2025/26) and tuition fees will be paid. We expect the stipend to increase each year. The start date is October 2026.

Applications will be considered on a rolling basis until the position is filled.

Canonical nucleotides constitute the building blocks for the biomolecules of life. They are integral components of oligonucleotides that encode the proteins required to control biological processes. Structurally modified nucleotides provide cornerstone building blocks for derived oligonucleotide (or nucleic acid) therapeutics that commonly target mRNA to perturb the production of disease-related proteins.[1,2] Oligonucleotide therapeutics are an emergent drug modality and consist of modified or unmodified short nucleic acid sequences; these include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNA (miRNAs), aptamers, and DNAzymes.[3] Notable recently also is the use of oligonucleotide sequences (mRNA) in the development of a vaccine for SARS CoV 2. Currently, twenty-two oligonucleotide therapeutics have been granted new drug approval by the U.S. Food and Drug Administration and many more are in the advanced stages of clinical trials.[4]

To meet a growing demand for RNA based therapeutics, new modalities and more efficient, sustainable and cost-effective synthetic methods to produce them are urgently needed.[5] To this end, several groups have developed complementary biocatalytic strategies exploiting terminal deoxyribonucleotidyl transferases (TdTs), RNA, DNA and Poly(U) polymerases that can extend RNA sequences using nucleoside triphosphate (NTP) building blocks.[6,7] Moreover, biocatalysis is now primed to unlock efficient routes to synthesis these requisite NTPs. Herein we will develop a biocatalytic approach to nucleoside triphosphates containing non-canonical ribose. Building upon the supervisor’s complimentary research expertise in this area (https://millerresearchgroup.co.uk & https://www.lovelockresearchgroup.co.uk),[8,9] 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 nucleotide chemistry, biocatalysis and protein engineering, all geared towards the design and development of routes to the 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.

References:
(1) Nat. Rev. Drug Discov. 2013, 12, 447–464. https://doi.org/10.1038/nrd4010.
(2) Molecules 2020, 25, 2050. https://doi.org/10.3390/molecules25092050.
(3) ACS Cent. Sci. 2020, 6, 672–683. https://doi.org/10.1021/acscentsci.0c00489.
(4) ACS Central Sci 2021, 7, 1980–1985. https://doi.org/10.1021/acscentsci.1c00608.
(5) Cell Rep. 2015, 11, 1018–1030. https://doi.org/10.1016/j.celrep.2015.04.031.
(6) Nat. Biotechnol. 2017, 35, 238–248. https://doi.org/10.1038/nbt.3765.
(7) Nat Nanotechnol 2021, 16, 630–643. https://doi.org/10.1038/s41565-021-00898-0.
(8) Nat Commun. 2026, 17, 622. https://doi.org/10.1038/s41467-025-67366-4.
(9) Angew. Chem. Int. Ed. 2024, 63, e202405040. https://doi.org/10.1002/anie.202405040.

To apply, please contact the main supervisor, Prof Gavin Miller - gavin.miller@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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