本课题组从长白山野生北虫草固体发酵菌丝体中提取出虫草素。该化合物即能降低败血症致死率，又具有肝保护作用。因此虫草素衍生物的构效关系和防治败血症并发急性肝功能衰竭作用机制研究具有重要意义。基于针对LPS 信号通路关键环节进行目标明确的阻断和调节，遏止LPS 所致器官衰竭等病理发展进程，达到防治败血症并发器官衰竭思路，本课题拟以虫草素为先导化合物，设计合成其衍生物，对所合成的衍生物进行进行整体动物药效学和分子水平的活性筛选，发现即能降低小鼠致死率，又能抑制TNF-α等炎症因子的虫草素衍生物，观察对其对肝功能衰竭小鼠的保护作用和对LPS 刺激巨噬细胞产生炎症反应的影响，从识别受体、胞内信号转导分子及核转录因子、下游炎症产物等层次分别探讨对LPS 诱导的TLR4 信号通路上几个重要分子，揭示防治败血症并发急性肝功能衰竭作用机制。本研究成果将为防治败血症并发急性肝功能衰竭的候选药物研究提供科学依据。

Cordycepin was separated as a major constituent of Cordyceps militaris that had been found to protect against sepsis-associated acute liver failure induced lethality in mice and had hepatoprotective properties. In this study we will synthesize cordycepin derivatives for study and evaluate their potential utility in combating experimental sepsis-induced acute liver failure, inhibiting TNF-α and nitric oxide levels using both in vivo and in vitro screening assay systems. In potential mechanisms study, the effect of selected active cordycepin derivatives on recognition receptors of LPS signaling pathways, p38 mitogen-activated protein kinase (p38MAPK), AP-1, nuclear factor-κB-p65 (NF-κB-p65) and downstream inflammatory factors TNF-α, NO, cytokines, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) will be observed in sepsis-associated acute liver failure mouse model. To investigate the molecular mechanisms in LPS-induced RAW 264.7 macrophages, the effects of active compounds on recognition receptors of LPS signaling pathways, the expression of LBP, CD14, TLR4, IKK, IκB, NF-κB mRNA, and protein levels of TLR4, p38, P65, c-jun, c-fos, and the concentration of TNF-α and cytokines will be measured. This research results will establish the theories basis for new medicine research and development of the prevention and treatment sepsis-associated acute liver failure.