(BioProcess) Harnessing Biocatalysis Toward Next Generation Nucleoside Triphopshates

About the Project

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.

About the programme

Join experts in industry and academia working to sustainably manufacture the complex and diverse molecules needed by modern society.

Industrial manufacturing is at a turning point. Many conventional production routes rely on non-renewable resources, harmful chemicals, and energy-intensive steps. Biocatalysis using engineered enzymes offers a proven solution.

Led by The University of Manchester in collaboration with AstraZeneca, The Universities of Bristol and York alongside other leading industrial partners, BioProcess aims to train the next generation of scientists in the skills needed to realise full the potential of biocatalysis, protein engineering and biomanufacturing for the UK bioeconomy.

Training

BioProcess aims to train the next generation of bio-innovators. Our interdisciplinary programmes prepare PhD students and researchers with the real-world skills to apply biocatalysis, protein engineering and sustainable manufacturing in industry.

We offer:

• PhD projects co-developed with industry and aligned with real manufacturing challenges
• advanced theoretical and practical skills training provided by a mixture of industry and academic project partners covering structural biology; biophysical and analytical methods; computational modelling; directed evolution; process modelling and development; digital skills
• Access to a network of elite partners and mentors
• A strong track record of impact, including a free online course in industrial biotechnology with over 10,000 learners to date.

Strong foundations in Biocatalysis:

Formerly CoEBio3, our centre has a focus on delivering solutions with real impact in pharmaceutical and chemical manufacturing with our industry partners. Our work has already enabled major industrial advances

Commercialised over 1,000 enzymes

• Covering 20+ reaction types, significantly expanding biocatalytic options for manufacturing.

Pioneered metal-free processes

• Reducing reliance on costly and hazardous precious metal catalysts.

Delivered high-performing biocatalysts

• Engineered industry-ready enzymes suitable for large scale pharmaceutical manufacturing.

We’ve also helped shape national policy. In 2018, our researchers co-authored the UK strategy report Growing the UK Industrial Biotechnology Base, supporting government plans for a £440 billion bio-economy by 2030.

Eligibility

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.

How to apply

To be considered for this project you’ll need complete a formal application through our online application portal.

Applications should be submitted through the BioProcess IDLA Website (https://www.mib.manchester.ac.uk/research/centres/coebio3/), where you can find a step-by-step guide to the process. Further information about the IDLA is also available. Informal enquiries can be made by emailing sarah.shepherd@manchester.ac.uk.

Please see individual project deadlines. Applications received after the deadline will not be considered.

Funding Notes

Successful applicants will be awarded a 4-year studentship covering:

• Tuition fees paid at Home student rate*
• A tax-free stipend to help with living costs, set at the UKRI minimum rate
• A Research Training and Support Grant to cover travel expenses and project consumables associated with your research including conference attendance, secondments, and other research and training activities
• A flexible budget for personal development and training

Additional funding is available to support a range of IDLA activities, such as institutional visits, outreach and hands-on practical training.

*A limited number of IDLA studentships may be awarded to international students each year. We strongly encourage international applicants to discuss tuition fee waivers during the interview stage, so that potential fee reductions or additional scholarship support through the host university can be explored. Any waiving of international fees will be considered on a case-by-case basis by the host institution.