具有PCSK9调控作用的天然产物的发现及其作用机制研究

Hyperlipidemia is a major risk factor of atherosclerosis which greatly threatens human health. Even though statins have a good efficacy and safety, some medical need is still unmet. With the patents of statins expiring, R&D of new type lipid-lowering drug is impending. PCSK9 is one of the most promising target by far, and its inhibitors are anticipated to be the new revolutionary lipid-lowering drugs. Pharmacological investigation indicated hyperlipidemia is closely related to stasis syndrome of TCM, thus it is potential to discover hits or leads from TCM with stasis-dissolving function. In our preliminary work, dozens of natural products with diverse skeletons and mechanisms on PCSK9 were found from some medicinal plants folkly used for stasis-dissolving. In order to obtain more hits or leads for lipid-lowering, several medicinal herbs such as Euphorbia helioscopia , Trichosanthes cucumeroides and Celastrus orbiculatus will be investigated chemically and pharmacologically. By virtue of isolation, derivatization and QSAR analysis, a mini-type compound library with chemical and biological diversity on PCSK9 modulation will be set up, aiming to develop a small-molecule PCSK9 modulator.

高血脂症是造成动脉粥样硬化的主要危险因素，严重危害人类健康。随着几个他汀类“重磅炸弹”药物专利的到期，新型降脂药物的研发迫在眉睫。PCSK9是目前最具有开发前景的降脂靶点，其抑制剂有望成为新的革命性降脂药物。现代医学认为，高脂血症与中医学中的“瘀症”密切相关，因此，可从具有散结化瘀功效的传统中药中寻找和开发降脂药物。本课题组前期通过对几种具有散结化瘀功效的传统中药的化学成分及药理活性研究，发现了几类具有降脂活性的天然产物，且初步的蛋白表达实验显示，它们对PCSK9的调控作用机制不同。本课题拟在前期研究基础上，从泽漆、土瓜根、南蛇藤等具有散结化瘀功效的药用植物中寻找和发现结构丰富多样的具有降脂活性的天然产物，阐明其构效关系，并深入研究其作用机制，最终建立天然来源的小分子PCSK9调控剂的化合物库，为新型降脂药物的研发奠定基础。

我们通过建立体外降脂筛选模型，对化瘀散结药用植物库进行筛选，建立了具有降脂作用的植物库。通过对泽漆，王瓜根，南蛇藤进行成分研究以及对化合物库的活性筛选，建立了包含十几种骨架的天然小分子降脂库。我们首次报道了假白榄烷型二萜和葫芦烷型三萜的降脂活性，且对PCSK9的调控作用机制存在差异。通过深入机制研究，建立天然来源的小分子PCSK9调控剂的化合物库，发现了较为新颖的抑制PCSK9分泌的抑制剂。此外，通过系统活性评价获得了具有开发前景的候选新药。“三库”的建立，彼此联系，互为补充，拓展了药用植物及天然产物的资源，为新型降脂药物的研发奠定基础。