山鸡椒中基于靶向调控NLRP3炎症小体新型活性成分的发现

NLRP3 inflammasome, a multiple protein complex composed of innate immune sensor NLRP3, ASC, and caspase-1, plays a key role in innate immunity and inflammation. The aberrant NLRP3 inflammasome activation contributes to the progress of several human diseases. Thus, NLRP3 inflammasome has been emerged as attractive chemotherapeutic targets in inflammatory diseases. Litsea cubeba used in traditional Chinese medicine for treatment of inflammatory diseases, while the active constituents and mechanism of action are still unclear. In our previous studies, we found one lignan showed inhibitory activity of caspase-1 and the secretion of IL-1β, and suppressed the activity of NLRP3 inflammasome which was mediated by ATP. On the basis of the above findings, a systematic and in-depth investigation of the low polar activity fractions will be carried out. The bioactivity-directed fractionation combined with CombiFlash and HPLC-NMR/HTC online detection were applied to discover compounds with novel structures and inhibitory activity of NLRP3 inflammasome. Furthermore, chemical conversion and biotransformation methods will also be explored to supply the optimization of leading compounds of NLRP3 inflammasome inhibitors. This study is hopefully to lay a foundation of elucidating the chemical entities of L. cubeba which served to reveal the active constituents of traditional Chinese medicines and provide basis for the innovative drug development, and it will also provide scientific basis for the development of a new therapeutic in NLRP3-driven inflammatory diseases.

NLRP3炎症小体的失调导致多种疾病的发生，基于NLRP3炎症小体靶向调控是发现抗炎药物的重要途径之一。中药山鸡椒在临床上用于炎症疾病的治疗，疗效确切，但药效物质不明确。本课题组前期确证了山鸡椒枝乙醇提取物的分离组分具有显著的抗炎活性，并发现1个具有显著抑制NLRP3炎症小体活化的木脂素类化合物，表明该部位存在值得进一步深入研究的新型抗炎活性成分。本项目拟在此基础上，集成运用CombiFlash和HPLC-NMR/HTS等分离和结构鉴定的现代新型技术方法，深入系统研究山鸡椒枝中抑制NLRP3炎症小体活化的活性成分，发现新颖结构类型的强活性化合物，阐明其精确结构和药理活性，探索转化合成的制备方法和构效关系，以期发现新型的NLRP3炎症小体抑制剂，为阐明山鸡椒的药效物质和新型抗炎创新药物研发奠定基础，同时也为炎症疾病的发病机制深入阐明提供重要依据。

NLRP3炎症小体的失调导致多种疾病的发生，基于NLRP3炎症小体靶向调控是发现抗炎药物的重要途径之一。围绕中药山鸡椒枝乙醇提取物乙酸乙酯萃取部位剩余的抗炎活性组分，以NLRP3炎症小体为靶标，集成运用CombiFlash和HPLC-NMR/HTS等现代色谱学方法和波谱学技术深入系统研究山鸡椒中抗炎强活性成分，共分离鉴定了65个化合物，其中新微量成分11个，发现具有显著抗炎活性成分6个；在此基础上，对前期获得具有显著抗炎活性的新型异喹啉类生物碱化合物进行了全合成和结构衍生化研究，已合成目标化合物及其衍生物共9个。进一步药效评价，遴选出抗炎候选化合物1个，并初步阐明了它的作用机制，目前对它已开展深入的成药性研究。抗炎候选药物的发现，阐明了山鸡椒“消肿止痛”部分药效物质基础，为揭示中药的科学内涵提供了重要依据，也为中药来源创新药物的研究奠定了重要基础。研究结果在国内外重要期刊发表研究论文4篇，申请中国发明专利1项；获得中国专利授权1项。项目培养期间，项目负责人入选中华中医药学会青年人才托举工程项目。