我们从海洋来源的链霉菌THS-55培养物中分离出一种新型抗菌素新抗菌素生物碱抗菌素A2c(AE)。通过广谱波谱鉴定了其化学结构，并阐明了其在HPV感染的宫颈癌中的特定机制。采用菌落形成实验、细胞周期分析、荧光染剂hoechst33342染色实验等方法，检测了AE对宫颈癌细胞的抑制作用。同时，采用流式细胞术、西方印迹、免疫沉淀、RNA干扰和分子对接等方法分析了AE的作用机制。AE在体外对HPV转化的宫颈癌HeLa细胞系表现出强大的细胞毒性。AE抑制了HeLa细胞的增殖，阻滞了细胞周期分布，并通过启动依赖于caspase的凋亡途径诱导细胞凋亡。进一步的研究揭示，AE诱导的凋亡通过降解E6/E7致癌蛋白介导。分子机制研究表明，AE通过活性氧(ROS)介导的泛素依赖蛋白酶体系统激活降解E6/E7致癌蛋白的水平，而增加的ROS产生是由于线粒体功能破坏引起的。本研究揭示了这种新型海洋来源的抗菌素生物碱可以靶向线粒体并降解HPV E6/E7致癌蛋白，并有潜在应用于宫颈癌细胞的引物化合物设计和开发，以及分析E6/E7功能的工具化合物开发的可能性。版权所有 © 2023. Elsevier Inc.出版。

Novel antimycin alkaloid antimycin A2c (AE) was isolated from the culture of a marine derived Streptomyces sp. THS-55. We elucidated its chemical structure by extensive spectra and clarified the specific mechanism in HPV infected-cervical cancer.Colony formation assay, cell cycle analysis, hoechst 33342 staining assay, et.al were used to detect the inhibitory effect of AE on cervical cancer cells. Meanwhile, flow cytometry, western blotting, immunoprecipitation, RNA interference and molecular docking were used to analyze the mechanism of AE.AE exhibited potent cytotoxicity in vitro against HPV-transformed cervical cancer HeLa cell line. AE inhibited the proliferation, arrested cell cycle distribution, and triggered caspase dependent apoptosis in HeLa cells. Further studies revealed AE-induced apoptosis is mediated by the degradation of E6/E7 oncoproteins. Molecular mechanic investigation showed that AE degraded the levels of E6/E7 oncoproteins through reactive oxygen (ROS)-mediated ubiquitin-dependent proteasome system activation, and the increased ROS generation was due to the disruption of the mitochondrial function.This present work revealed that this novel marine derived antimycin alkaloid could target the mitochondria and subsequently degrade HPV E6/E7 oncoproteins, and have potential application in the design and development of lead compound for cervical cancer cells, as well as the development for tool compounds to dissect E6/E7 functions.Copyright © 2023. Published by Elsevier Inc.