Synthetic approaches to developing new pharmacological modulators for P2X7 receptors (STOKESU18DTP2)

Ginseng is a medicinal herb used in traditional medicine in Asia for thousands of years. In traditional Chinese medicine practices it is an “all healing” tonic thought to have many beneficial effects including stimulating the immune system. The pharmacologically active constituents of ginseng are known as ginsenosides and there are over 30 different chemicals present. We recently discovered that several protopanaxadiol ginsenosides, including the major in vivo metabolite (ginsenoside CK) act as positive allosteric modulators of the P2X7 ion channel. The action of ginsenosides reduces the concentration of the ligand ATP required for channel activation and enhances downstream signalling pathways including an increase in macrophage cell death. This action of ginsenoside CK on P2X7 may underlie some of the reported immune boosting actions of ginsenosides in vivo. In this PhD project we will explore the structure-activity relationship of the interaction between protopanaxadiol ginsenosides and P2X7. We have a basic idea of which chemical groups are required for activity at this ion channel (Helliwell et al, 2015; British Journal of Pharmacology) and will explore this further using two approaches. The first is a semi-synthetic chemistry approach in collaboration with an experienced medicinal chemist Professor Ganesan. The second is a biosynthetic approach in collaboration with an experienced plant biologist Professor Anne Osbourn (JIC). During this project we will design and generate novel analogues of ginsenosides to test for improved activity at the P2X7 receptor. The student will be trained in a number of medicinal chemical and biological techniques in different laboratories gaining a unique expertise in natural product pharmacology and drug discovery.

This project has been shortlisted for funding by the Norwich Biosciences Doctoral Training Partnership (NRPDTP). Shortlisted applicants will be interviewed as part of the studentship competition. Candidates will be interviewed on either the 9th, 10th or 11th January 2018.
The Norwich Biosciences Doctoral Training Partnership (NRPDTP) offers postgraduates the opportunity to undertake a 4 year research project whilst enhancing professional development and research skills through a comprehensive training programme. You will join a vibrant community of world-leading researchers. All NRPDTP students undertake a three month professional internship (PIPS) during their study. The internship offers exciting and invaluable work experience designed to enhance professional development. Full support and advice will be provided by our Professional Internship team.
For further information and to apply, please visit our website: www.biodtp.norwichresearchpark.ac.uk

For more information on the supervisor for this project, please go here: https://www.uea.ac.uk/pharmacy/people/profile/l-stokes
Type of programme: PhD
Start date of project: 1st October 2018
Mode of study: Full time
Length of studentship: 4 years

Students with, or expecting to attain, at least an upper second class honours degree, or equivalent, are invited to apply.