Competitive EPSRC funded PhD in Chemistry: Sustainable synthesis of antiviral and anticancer drugs through chemoenzymatic routes

Sustainable synthesis of antiviral and anticancer drugs through chemoenzymatic routes

Nucleoside analogues (NAs) have been in clinical use for almost 50 years and are the cornerstone for the treatment of cancer or viral infections. NAs must undergo three in vivo phosphorylations in a stepwise manner to yield the corresponding active nucleoside triphosphate analogue (NTP), which exerts the therapeutic effect. Unfortunately, NAs suffer from many drawbacks such as poor cellular uptake because of insufficient expression of membrane transporters, premature breakdown, and slow conversion to the triphosphate form due to rate-limiting first phosphorylation step catalysed by nucleoside kinase (NK). Therefore, monophosphorylated NA prodrugs have been extensively studied leading to several FDA-approved medicines. However, some NAs have been reported to suffer from a second or third slow and inefficient phosphorylation step, respectively catalysed by nucleoside monophosphate kinase (NMPK) and nucleoside diphosphate kinase (NDPK). These analogues are often associated with toxicity or low efficacy due to their mono- and diphosphate forms accumulation or metabolic deactivation respectively. In addition, for many other NAs in the literature, the detailed metabolism to yield the NTP is still not known. Interestingly, the design of higher phosphorylated NA prodrugs is relatively underexplored with only few examples reported and currently a drug to bypass the whole phosphorylation cascade does not exist. These new approaches require the synthesis of NMP and NDP, and then reaction with a monophosphorylating reagent to incorporate the last phosphate group bearing the masking groups. In general, the vast majority of nucleoside and nucleotide analogues are synthesized chemically. Despite the progress achieved in the development of chemical methods, their preparation remains a challenging problem. Disadvantages of these multistep synthesis are long reaction times, toxic reagents, low yields, and tedious purification protocols. In addition, limited regioselectivity leads often to the formation of different phosphorylation products, while some nucleotide products harbouring sensitive functional groups are not accessible using these approaches.

In this scenario cascade biocatalysis, which is emerging as a powerful tool to obtain pharmaceuticals from readily available materials using natural or evolved enzymes, could offer a valid alternative to access nucleotides analogues.

Aim

Taking advantage of the recent efforts in enzyme discovery and protein engineering by rational drug design toward nucleosides or nucleotides, this work aims to develop a chemoenzymatic route that gives access to nucleotide analogues.

The project involves the use of natural or engineered nucleoside kinases to prepare mono and diphosphate species then can be converted chemically into their corresponding di- and triphosphate prodrugs. It will explore the possibility to merge NK and NMPK activity by creating a dual-function biocatalyst, capable of performing both phosphoryl-transfer reactions. Finally, it will investigate the possibility to use engineered enzymes for the synthesis of the prodrugs.

Research environment, training, and development opportunities:

This interdisciplinary project will provide training in modern synthetic methodology, medicinal chemistry and biocatalysis.

We are looking for an enthusiastic, talented, and self-motivated individual with an organic chemistry background (or closely related discipline) with a passion for sustainable ways to create new medicines, to join our chemoenzymatic project within Cardiff School of Chemistry.

This project will allow you to obtain valuable training and to acquire knowledge and tools related to the broader aspects of your research such as sustainability and responsible research and innovation.

Several impactful publications are expected to result from this PhD-project, and you will be expected to take an active part in their preparation. You will also be encouraged to help disseminate the work where possible through conference presentations, posters and online/social media.

English Language

If English is not your first language that you must fulfil our English Language criteria before the start of your studies. Details of accepted English Language qualifications for admissions can be found here English language requirements for postgraduate students – Study – Cardiff University

Supervisors

Dr Michaela Serpi

Dr Guto Rhys

Professor Ian Fallis

Deadline for applications – Monday 14th October

Start date – 1st January 2025 or 1st April 2025 only.

How to apply

All applications should be submitted via the online application portal Chemistry – Study – Cardiff University

As part of your application please include:

CV

Guidance on CVs for a PhD position can be found on the How to Write an Effective PhD CV PhD Applications (findaphd.com)

Personal statement

Ensure your personal statement provides a clear explanation of your research interest, preparation undertaken, and an understanding of the project. 

Your personal statement should be no more than 500 words, and address the following questions:

1. What are your scientific research interests and ambition?

2. How has your academic and/or professional journey prepared you for PhD study? (for instance, give examples of work you particularly enjoyed, of challenges you overcame, of connecting with others about your work or ideas, of showing inventiveness, of developing new skills and knowledge)

3. Why do you think this project is important?

If you do not include a CV and personal statement your application will not be considered.

You can also review our Cardiff University webpage about EPSRC funded posts –EPSRC – Study – Cardiff University

Overview of projects – competitively funded

This is a competitively funded project, and only one applicant across all our Chemistry EPSRC projects will be successful. You can apply for more than one project in Chemistry on the same application, but must list all the projects on your application clearly, and provide a separate supporting statement for each post.

EPSRC DTP studentships are available to home and international students. Up to 30% of our cohort can comprise international students, this is allocated on a competitive basis, with the funding being allocated to the best international applicants across the University.

The other projects can be found here:

Competitive EPSRC funded PhD in Chemistry: Small Molecule Activation and Valorisation Using Low-Coordinate Complexes at Cardiff University on FindAPhD.com