绵马贯众中新颖酚类成分的发现及其抗RSV作用机制研究

More than half (60%-70%) of human infectious diseases are caused by viral infection. Presently, most of the antiviral drugs used in the clinical or under-researched focus their targets on the viruses, but which show narrow-spectrum antiviral activity and easily lead to drug resistance. Whereas, drugs targeting host-related proteins or genes would avoid these problems, thus which are more needed in the clinical especially when some specific drugs lack effect and new viruses spread. Respiratory syncytial virus (RSV) is the most common respiratory infective virus except influenza. However, there is still no common and safe treatment for RSV infection. The rhizome of Dryopteris crassirhizoma is an important and common traditional Chinese medicine used for the treatment of kinds of infectious diseases. Our investigation on the characteristic constituent from the rhizomes of Dryopteris crassirhizoma led to the isolation and identification of kinds of compounds with novel structural skeletons. Among the isolates, some exhibited obvious inhibitory effect on all the testing viruses, and the most significant on RSV. Preliminary study on the mechanism of anti-RSV action of compound 37 which showed stronger activity than the positive control ribavirin was performed. It demonstrated that 37 could prevent the virus’s replication in the cytoplasm of the cell and not easily lead to drug resistance, indicating that the target of 37 was the host protein or gene but which was different from that of ribavirin. Thus, in the present study, we will make our continuing efforts to perform further study on the phenolic components from the rhizomes of Dryopteris crassirhizoma, discovering more active antiviral compounds, analyzing the structure-activity relationship, and exploring the new anti-RSV mechanism targeting the host cell. This study will provide the scientific support for developing new anti-RSV leading compounds.

人类60%-70%的传染病由病毒感染引起。目前临床使用及研发中的抗病毒药物多靶向病毒，但其抗病毒谱窄且易产生耐药。当新型病毒株和耐药性的不断出现时，则亟需以宿主为靶点的抗病毒药物。呼吸道合胞病毒 (RSV) 是除流感外最常见的呼吸道感染病毒，暂无理想防治手段。绵马贯众为我国传统中药，用于治疗多种感染性疾病。我们前期研究发现其中含有多种结构新颖的酚类成分，且部分对多种病毒均表现出明显抑制活性，对RSV的作用最为显著。初步抗RSV作用机制研究显示，活性强于阳性对照药利巴韦林的化合物37可干扰病毒在细胞内的复制，不易使病毒产生耐药，提示37是通过靶向宿主而发挥抗病毒活性，但其作用机制不同于利巴韦林。故本项目拟在前期基础上，进一步对绵马贯众中的酚类成分进行分离鉴定和活性评价，探讨构效关系，寻找活性化合物抗RSV作用的宿主靶点，阐明其作用机制，为研究和开发新型抗RSV先导化合物提供科学依据。

呼吸道合胞病毒（RSV）是除流感病毒外最常见的呼吸道感染病毒，也是婴幼儿、老年人和免疫功能低下者诱发下呼吸道感染的主要病原。目前临床上批准治疗RSV感染的药物为核苷类似物利巴韦林和RSV F蛋白抗体帕利珠单抗，但均在临床应用中具有较大的局限性。因此，亟需研发新型抗RSV药物，特别是靶向宿主的抗病毒药物。本课题组在前期研究中发现，常用传统中药绵马贯众中含有多种结构新颖的酚类成分，部分结构对多种病毒均表现出明显抑制活性，其中对RSV的作用最为显著。本研究在前期基础上，继续对绵马贯众的化学成分进行分离纯化，同时对同属植物暗鳞鳞毛蕨的化学成分也进行了系统研究；并对所得到的大部分单体进行了抗病毒活性评价。结果显示，绵马贯众中的活性化合物37可能通过作用于病毒宿主细胞干扰RSV L蛋白的合成而发挥抗病毒活性，Hsp90可能为其潜在的作用靶点，但具体确切的作用机制还有待进一步的深入研究；而暗鳞鳞毛蕨中也同样富含结构新颖的间苯三酚类成分，其结构类型与绵马贯众中的具有较大区别；暗鳞鳞毛蕨的间苯三酚类成分除了具有抗病毒活性外，对病毒引起的炎症反应也有较强的抑制作用，但其具体的作用机制也有待继续研究。本研究通过对两种鳞毛蕨属药用植物进行化学成分研究，得到了多种结构新颖的酚类成分，丰富了该属植物的化学成分多样性，同时也为后续的药理活性研究提供了物质基础；对所得到的化学成分进行了抗病毒及其抗炎等活性的评价，以期寻找作用于宿主的抗病毒天然产物，为后续相关深入研究提供了指导作用，也为促进该两种药用植物的研究和开发起到了一定的推动作用。