五环三萜的"药物再定位"：其降脂作用的分子机制、结构优化及新药发现研究

Hyperlipidemia and related atherosclerosis (AS) are serious diseases damaging human health. Statins are the most popular and commonly prescribed cholesterol-lowering agents, however they have serious side effects such as liver damage,muscle pain and rhabdomyolysis, and thus there are urgent needs in search of novel non-statin hypolipidemic drugs. In previous studies, oleanolic acid and related pentacyclic triterpenes exhibited significant cholesterol-lowering effect and anti-AS activity, and their potency was even similar to that of statins. Preliminary mechanistic studies show that oleanolic acid, at least in part, exerts its lipid-lowering effect through inhibition of cholesterol biosynthesis.In addition, we noticed an interesting and important fact: the biosyntheses of pentacyclic triterpenes in plants and cholesterol in human/vertebrates both employ oxidosqualene cyclases (OSC)-catalyzed cyclization as the key step. In the above regards, we hypothesize that oleanolic acid and related pentacyclic triterpenes are very likely product analogue inhibitors of OSC, that is to say, they might exert cholesterol-lowering effect through OSC inhibition thus allowing for inhibition of cholesterol biosynthesis. Aming at the hypolipidemic effect of pentacyclic triterpenes, this project focuses on the mechanistic studies, rational drug design, synthesis, and drug discovery.We hope to get creative achievements in basic research related with drug repositioning of pentacyclic triterpenes, and to obtain new type of drug candidates as non-statin hypolipidemic agents.

高血脂症及其诱发的动脉粥样硬化（AS）是严重危害人类健康的常见病。他汀类药物是目前临床应用最广泛的降脂药，但其具有肝损害、肌痛和横纹肌溶解等副作用，因而迫切需要研制新型非他汀类降脂药。前期研究表明，齐墩果酸等五环三萜具有极显著的降脂和抗AS功效，其活性甚至与他汀类药物相当！初步的机制研究表明，齐墩果酸至少是部分通过抑制胆固醇的生物合成而实现降脂功效。另一方面，一个有趣而重要的事实是：植物体内五环三萜和人/脊椎动物体内胆固醇的生物合成均采用"氧化角鲨烯环合酶（OSC）"催化的环合反应作为关键步骤。据此，我们提出一个全新假设：五环三萜可能是OSC产物类似物抑制剂！其降脂作用可能是通过抑制OSC进而抑制胆固醇的生物合成而实现的。本课题针对五环三萜的降脂作用，开展作用机制、合理药物设计、合成及新药发现研究，期望在五环三萜"药物再定位"相关的基础研究方面取得创新性成果，并获取非他汀类降脂候选新药。

本项目初步揭示了五环三萜降血脂及抗非酒精性脂肪肝作用的分子机制和靶标，首次发现齐墩果酸等五环三萜可能通过激活AMPK-ERR轴而发挥抑制脂质生物合成、促进线粒体氧化代谢及抗炎抗纤维化作用。为研制新型降血脂、抗脂肪肝及其他炎症性代谢性疾病新药奠定了坚实基础。本项目相关成果共发表基金标注SCI论文12篇，其中，影响因子>5的论文4篇，单篇最高影响因子为13.038；申请发明专利4件；“齐墩果酸片的抗非酒精性脂肪肝的临床疗效验证”获得南京医科大学第一附属医院的伦理审查批准件，并即将开展临床验证试验。五环三萜更深入的作用机制、靶标确证及新药研究正在进行中。