代谢综合征已成为威胁全球的公共健康问题，新治疗药物的开发刻不容缓。前期研究中我们发现了一个来源于西藏白肉灵芝的杂萜GL-1具有显著的降脂和改善胰岛素抵抗活性，GL-1是新型的α-葡萄糖苷酶抑制剂，并能够改变高血糖小鼠肠道菌群的组成。结合代谢综合征涉及多个组织或细胞的特点，本项目以发现靶向肠道、活性多样，具有治疗代谢综合征的候选化合物为研究目标。以GL-1为模板分子，针对活性基团进行结构改造、优化，并结合活性筛选及分子反向对接等计算机虚拟筛选方法进行构效关系分析，优化并合成具有新颖结构的活性杂萜类衍生物；以降糖、降脂动物模型评价杂萜衍生物的药理作用活性；以肠道菌群为靶点，从肠道菌群的组成、肠道营养成分的分布、肠道激素、肠道代谢物、及小肠上皮细胞转录组等方面解析活性衍生物的作用机制。该研究工作可以明确活性衍生物作用于肠道菌群改善代谢综合征的机制，同时有望得到新的机制清楚明确的药物候选化合物。

Metabolic syndrome is becoming a worldwide health problem, and is a multifactorial disease dependent on a complex interaction of host genetics, diet, and other environmental factors. In the previous study, we found GL-1 isolated from Ganoderma leucocontextum exerted potent and efficacious hypoglycemic, hypolipidemic, and insulin-sensitizing effects, and modulated the composition of gut microbiota. Based on these results, we would like to optimize GL-1 to find “multi-target” leading compounds through the structure-activity relationship analysis, and evaluate the activities by High-fat diet-fed mice, ob/ob diabetic mice and db/db diabetic mice, and then sought to determine whether the activities of leading compounds were related to changes in the gut microbiota. Our study could clarify the mechanism of active derivatives targeting on the gut microbiota to improve the metabolic syndrome, and might to find a promising candidate for new drug developments.