肾癌对放疗化疗均不敏感，肾癌新药研发急需新靶点新机制的抗肾癌先导化合物。基于化学蛋白质组学和转录组学技术，我们发现海洋微生物来源粉蝶霉素苷元可通过作用PRDX1等新型特异性靶点，对肾癌细胞具有选择性抑制活性，其代谢产物糖苷化合物毒性小，具有更好的成药性。本项目将在分离到的海洋微生物来源的一系列新结构粉蝶霉素糖苷中筛选高效低毒的抗肾癌活性化合物，利用表面等离子共振和化学蛋白质组学技术，捕捉和鉴定肾癌细胞内与糖苷相互作用的靶蛋白；利用转录组学技术，对糖苷作用肾癌/正常细胞前后的差异表达基因进行对比分析，用生物信息学分析和确定糖苷特异性作用肾癌细胞的靶基因；最后通过基因敲低/过表达等分子生物学方法进行特异性靶点的体外验证，阐明糖苷对肾癌细胞精准杀伤的新机制。本项目联合运用活性筛选和不同组学技术，聚焦于粉蝶霉素糖苷作用肾癌细胞的特异性靶点，为新型肾癌靶向药物研发提供海洋来源的新机制药物先导物。

Renal carcinoma is not sensitive to radiotherapy and chemotherapy, and new anti-tumor lead compounds are urgently needed for new drug discovery for renal cell carcinoma. In our previous study, several natural piericidin aglycones were isolated from marine microoganisms with selective inhibitory activities against renal carcinoma cell lines, and the specific targets, such as PRDX1, were identified with chemical proteomics and transcriptome techniques. Piericidin glycosides, the main drug metabolites of the aglycones, with less toxicity and better druggability, showed to be more valuable. In this project, the anti-renal carcinoma lead compounds with high efficiency and low toxicity will be screened in the natural piericidin glycosides obtained from marine microoganisms. The protein-molecular interactions will be studied by surface plasmon resonance (SPR) and chemical proteomics technique to catch the target proteins of the glycosides against renal carcinoma cell lines. Base on the transcriptomics and bioinformatics analysis, differentially expressed genes before and after drug (glycosides) action on renal carcinoma or normal tissue cell lines will be compared and analyzed. The specific drug targets of the piericidin glycosides will be determined and verified by knockdown and overexpression techniques of the target genes, and the new mechanism of selective inhibitory activities against renal carcinoma cell lines will be illuminated. With the combined utilization of natural product bioassay and various Omics technology, this project aims the specific drug targets of piericidin glycosides against renal carcinoma cell lines, and will provide marine-derived lead compound with new mechanism for new drug discovery for renal carcinoma.