Synthetic approaches to developing new pharmacological modulators for P2X7 receptors

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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.