新型抗菌肽嵌合体M(27-39)-HTPP靶向抗HCC作用及机制研究

家蝇作为一种卫生害虫，其自身独特免疫防御系统为药用活性分子发掘提供了丰富的资源。前期，课题组对家蝇抗菌肽cecropin进行构效关系研究时获得抗肝癌（HCC）活性更高、分子更小的衍生肽M27-39，并利用从疟原虫CSP筛选获得的肝靶向穿膜肽HTPP对其进行分子改造，成功构建新型靶向抗菌肽嵌合体M(27-39)-HTPP。体外实验证实M(27-39)-HTPP不仅可特异靶向肝脏并递送至癌细胞内，且抗HCC效果显著增强，但其体内抗HCC作用及具体机制不明确。本项目拟以肝癌原位种植瘤裸鼠为模型，研究M(27-39)-HTPP体内靶向抗HCC效果，在此基础上，通过研究其与肝癌细胞表面分子HSPG的关系阐明靶向机制，并围绕肝癌发生发展关键事件，通过针对不同潜在靶位点的实验设计，探讨其靶向抗HCC分子机制，为开发拥有自主知识产权的新型靶向抗肝癌药物提供基础，也为昆虫来源活性分子的多功能研究拓展视野。

Musca domestica, although a sanitary pest, has extremely unique immune defense system, which provides rich resources for the excavation of the medicinal active molecules. In carrying out the structure-activity studies of Musca domestica antimicrobial peptide cecropin (MDC), we have screened a small peptide M27-39, a derivative peptide with higher activity against hepatic carcinoma (HCC) and smaller molecular size than MDC. We have also modified the peptide M27-39 by using HTPP as a targeting vector to construct the targeted antimicrobial peptide chimera M(27-39)-HTPP. In previous studies, it was confirmed that M(27-39)-HTPP not only displayed liver-targeting function and could be delivered into the hepatoma cell, but also its anti-HCC effect was significantly enhanced compared with M27-39 by in vitro experiments. But the anti-HCC effect of M(27-39)-HTPP in vivo and the mechanism of the anti-HCC effect still need to clarify. This project intends to investigate anti-HCC activity of M(27-39)-HTPP in vivo using situ implantation of human hepatocellular carcinoma in nude mice at first. And then, we will clarify the targeting mechanism of M(27-39)-HTPP by studying its relationship with hepatoma cell surface molecule-HSPG. Finally, according to the key events in the process of hepatocellular carcinoma development, we will design the experiment aiming at different potential targets to intend to explore the molecular mechanism of M(27-39)-HTPP against HCC. If we can achieve the desired results, we will provide a new drug candidate molecule with the independence intelligent property right for the development of targeting anti-HCC drugs, and we will also expand the field of research for the multi-function study of active molecules from insect.