新型Hsp90抑制剂阻碍HSV-1组装与释放的分子机制研究

Herpes simplex virus type 1（HSV-1） is a widespread human pathogenic virus. It is urgent to develop novel antiviral agents because of the singleness of clinical used drugs and the emergence of drug resistant strains. We previously explored a novel Hsp90 inhibitor as an anti-HSV-1 agents, and the in vitro and in vivo experimental results suggested that Hsp90 inhibitors showed significant antiviral activity against HSV-1 standard strains and clinical drug resistant strains. But for the mechanism of action of Hsp90 inhibitors remains to be revealed. We hypothesized that Hsp90 inhibitors leading to viral proteins susceptible to degradation by inhibiting the interaction between Hsp90 and viral proteins, thereby affecting the virus particle localization within the cell, assembly and release. Thus, based on the previous research, this project will use Hsp90 inhibitors as molecular probes and focus on the following contents: research on the function of Hsp90 in the HSV-1 particles intracellular assembly and release process; detection of the interaction between Hsp90 and viral proteins; analyzing the role of Hsp90 in viral proteins Golgi localization process and the related molecular mechanism; explore the dynamic role of Hsp90 in the process of HSV-1 particles transport and release along the microtubule. This project will provide the foundation for the understanding and development of Hsp90 inhibitors as novel anti-HSV-1 agents.

单纯疱疹病毒Ⅰ型（HSV-1）是重要的人类致病病毒。针对目前临床治疗药物单一及不断出现的耐药现象，申请者以新型Hsp90抑制剂为研究对象，前期体内、外研究结果显示其对HSV-1标准株及临床耐药株均具有显著的抗病毒活性，但抗病毒作用机制尚不明确。Hsp90抑制剂可能通过影响Hsp90与病毒蛋白的相互作用，导致病毒蛋白降解，进而影响病毒颗粒的胞内定位、组装与释放。本项目拟在前期研究工作的基础上，以新型Hsp90抑制剂为小分子探针，进行如下研究：研究Hsp90在HSV-1胞内组装与释放中的作用；检测Hsp90与病毒蛋白的相互作用；分析病毒蛋白在高尔基体定位过程中Hsp90的作用及分子机制；探讨Hsp90辅助HSV-1颗粒沿微管骨架支运输与释放的作用；构建豚鼠皮肤疱疹模型测试新型Hsp90抑制剂动物体内抗HSV-1的作用。本课题将为Hsp90抑制剂作为新型抗HSV-1病毒药物的研究和开发提供基础。

虽然现今医药技术不断发展进步，但是单纯疱疹病毒Ⅰ型（HSV-1）由于其具有多种免疫逃逸机制和耐药性还是具有很高的感染率，所以需要进一步研究明确抗病毒作用机制和开发新型抗HSV-1药物。申请者在体内外水平上以Hsp90抑制剂作为研究对象，进一步阐明了其抗病毒作用机制和作为抗HSV-1新型药物的研究基础。申请者通过科研研究证明和综述了新型Hsp90抑制剂AT-533可阻碍HSV-1的组装和释放、Hsp90α维持HSV-1 VP16稳定性并调控α基因表达、新型Hsp90抑制剂AT-533可抑制HSV-1诱导的炎症、确定新型Hsp90抑制剂AT-533在C57小鼠皮肤带状疱疹模型中的抗病毒作用和Hsp90可作为候选的广谱抗病毒药物靶标。以上研究成果充分详实地展示了新型Hsp90抑制剂抗HSV-1的作用及机制，并为其作为新型抗HSV-1药物奠定了坚实基础。