PhD in Chemistry: Medicinal Chemistry of Nucleotide Analogues

Nucleoside analogues (NAs) are an important class of antiviral and anticancer agents commonly used in the therapy of many different viral infections and cancer conditions. To exert their biological activity, NAs must be phosphorylated (in vivo) via three consecutive phosphorylations to generate their triphosphate form (NTP), which is generally the active molecule. NTP analogues act by interfering with viral or human enzymes as competitive inhibitors of their natural substrates or by being incorporated into newly synthesized viral DNA and RNA strands. However, the stepwise intracellular transformation via the nucleoside mono- (NMP) and diphosphates (NDP) into the corresponding NTP often occurs insufficiently because NAs suffer of many drawbacks such as poor uptake, slow phosphorylation, and premature breakdown. Furthermore, many NAs have poor biological half-lives, variable bioavailability after oral administration or selection of drug resistance, which reduce their clinical efficacy. To overcome these limitations, the usage of prodrugs of NAs with a phosphate group or an isosteric and isoelectronic phosphonate moiety have been investigated. Some of these prodrugs were capable of delivering the monophosphorylated metabolite and prove able to offer advantages over the use of the corresponding NA. Some approaches have been more successful than other leading to FDA-approved therapeutics and clinical candidates. However, all these approaches delivered the monophosphor(n)ylated forms of the nucleosides that subsequently needed further phosphorylation into the corresponding NTP.

Aim: With this project we aim to investigate the development of novel prodrugs of NDPs and NTPs that would offer the advantage to releases directly NDPs and NTPs inside the cell. Such prodrugs will be more efficient in bypassing the phosphorylation steps normally needed for the activation of NAs and would maximize the intracellular concentration of the ultimately bioactive NTP.

The first objective of this project would be to identify a suitable synthetic route to prepare the NTP prodrugs of natural nucleosides, check their chemical stability and activation in biological matrix. Once we have this information, we will then apply the establish synthetic protocol to NAs of biological interest and assess their biological activity and activation pathway.

This project will help to develop skills in modern synthetic methodology and medicinal chemistry. The graduating PhD student will be fully equipped for a future career in the pharmaceutical industry.

Academic criteria

We require applicants to have a 2.2 BSc or equivalent to be considered for PhD study. Applications are particularly welcome from students with experience in medicinal chemistry

If English if not your first language then 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:

https://www.cardiff.ac.uk/study/international/english-language-requirements/postgraduate

How to apply

To apply please complete the online application and state the project title and supervisor name:

https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/chemistry 

Supervisor

Dr Michaela Serpi - People - Cardiff University

Cardiff University is committed to supporting and promoting equality and diversity and to creating an inclusive environment for all. We welcome applications from all members of the global community irrespective of age, disability, sex, gender identity, gender reassignment, marital or civil partnership status, pregnancy or maternity, race, religion or belief and sexual orientation.