Synthetic approaches to developing new pharmacological modulators for P2X7 receptors

开发 P2X7 受体新药理调节剂的合成方法

• 批准号: 2059870
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2059870
• 关键词: Synthetic; approaches; developing; new; pharmacological

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.

人参是一种草药，在亚洲传统医学中使用了数千年。在中国传统医学实践中，它是一种“所有愈合”的补品，被认为具有许多有益的效果，包括刺激免疫系统。人参的活性成分被称为人参皂苷，有超过30种不同的化学物质存在。我们最近发现，几个原人参二醇皂苷，包括主要的体内代谢产物（CYP 3CK）作为P2 X7离子通道的正变构调节剂。甘草苷的作用降低了通道激活所需的配体ATP的浓度，并增强了下游信号传导途径，包括增加巨噬细胞死亡。P2 X7的这种作用可能是一些报道的皂苷在体内的免疫增强作用的基础。在这个博士项目中，我们将探索原人参二醇皂苷和P2 X7之间相互作用的构效关系。我们对这种离子通道的活性需要哪些化学基团有一个基本的想法（Helliwell et al，2015; British Journal of Pharmacology），并将使用两种方法进一步探索这一点。第一种是与经验丰富的药物化学家Ganesan教授合作的半合成化学方法。第二种是与经验丰富的植物生物学家Anne Osbourn教授（JIC）合作的生物合成方法。在这个项目中，我们将设计和产生新的皂苷类似物，以测试P2 X7受体的活性改善。